Modulators of ATP-binding cassette transporters

ABSTRACT

The present invention relates to modulators of ATP-Binding Cassette (“ABC”) transporters or fragments thereof, including Cystic Fibrosis Transmembrane Conductance Regulator, compositions thereof, and methods therewith. The present invention also relates to methods of treating ABC transporter mediated diseases using such modulators.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 11/165,818, filed Jun. 24, 2005 which claims priority under 35U.S.C. §119 to U.S. Provisional Application No. 60/582,676, filed Jun.24, 2004 and entitled “MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS”,U.S. Provisional Application No. 60/630,127, filed Nov. 22, 2004 andentitled “MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS”, U.S.Provisional Application No. 60/635,674, filed Dec. 13, 2004 and entitled“MODULATORS OF ATP-BINDING CASSETTE TRANSPORTERS”, U.S. ProvisionalApplication No. 60/658,219, filed Mar. 3, 2005 and entitled “MODULATORSOF ATP-BINDING CASSETTE TRANSPORTERS”, and U.S. Provisional ApplicationNo. 60/661,311, filed Mar. 11, 2005 and entitled “MODULATORS OFATP-BINDING CASSETTE TRANSPORTERS”, the entire contents of each of theabove application being incorporated herein by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to modulators of ATP-Binding Cassette(“ABC”) transporters or fragments thereof, including cystic fibrosistransmembrane conductance regulator (“CFTR”), compositions thereof, andmethods therewith. The present invention also relates to methods oftreating ABC transporter mediated diseases using such modulators.

BACKGROUND OF THE INVENTION

ABC transporters are a family of membrane transporter proteins thatregulate the transport of a wide variety of pharmacological agents,potentially toxic drugs, and xenobiotics, as well as anions. ABCtransporters are homologous membrane proteins that bind and use cellularadenosine triphosphate (ATP) for their specific activities. Some ofthese transporters were discovered as multidrug resistance proteins(like the MDR1-P glycoprotein, or the multidrug resistance protein,MRP1), defending malignant cancer cells against chemotherapeutic agents.To date, 48 ABC Transporters have been identified and grouped into 7families based on their sequence identity and function.

ABC transporters regulate a variety of important physiological roleswithin the body and provide defense against harmful environmentalcompounds. Because of this, they represent important potential drugtargets for the treatment of diseases associated with defects in thetransporter, prevention of drug transport out of the target cell, andintervention in other diseases in which modulation of ABC transporteractivity may be beneficial.

One member of the ABC transporter family commonly associated withdisease is the cAMP/ATP-mediated anion channel, CFTR. CFTR is expressedin a variety of cells types, including absorptive and secretoryepithelia cells, where it regulates anion flux across the membrane, aswell as the activity of other ion channels and proteins. In epitheliacells, normal functioning of CFTR is critical for the maintenance ofelectrolyte transport throughout the body, including respiratory anddigestive tissue. CFTR is composed of approximately 1480 amino acidsthat encode a protein made up of a tandem repeat of transmembranedomains, each containing six transmembrane helices and a nucleotidebinding domain. The two transmembrane domains are linked by a large,polar, regulatory (R)-domain with multiple phosphorylation sites thatregulate channel activity and cellular trafficking.

The gene encoding CFTR has been identified and sequenced (See Gregory,R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). Adefect in this gene causes mutations in CFTR resulting in cysticfibrosis (“CF”), the most common fatal genetic disease in humans. Cysticfibrosis affects approximately one in every 2,500 infants in the UnitedStates. Within the general United States population, up to 10 millionpeople carry a single copy of the defective gene without apparent illeffects. In contrast, individuals with two copies of the CF associatedgene suffer from the debilitating and fatal effects of CF, includingchronic lung disease.

In patients with cystic fibrosis, mutations in CFTR endogenouslyexpressed in respiratory epithelia leads to reduced apical anionsecretion causing an imbalance in ion and fluid transport. The resultingdecrease in anion transport contributes to enhanced mucus accumulationin the lung and the accompanying microbial infections that ultimatelycause death in CF patients. In addition to respiratory disease, CFpatients typically suffer from gastrointestinal problems and pancreaticinsufficiency that, if left untreated, results in death. In addition,the majority of males with cystic fibrosis are infertile and fertilityis decreased among females with cystic fibrosis. In contrast to thesevere effects of two copies of the CF associated gene, individuals witha single copy of the CF associated gene exhibit increased resistance tocholera and to dehydration resulting from diarrhea—perhaps explainingthe relatively high frequency of the CF gene within the population.

Sequence analysis of the CFTR gene of CF chromosomes has revealed avariety of disease causing mutations (Cutting, G. R. et al. (1990)Nature 346:366-369; Dean, M. et al. (1990) Cell 61:863:870; and Kerem,B-S. et al. (1989) Science 245:1073-1080; Kerem, B-S et al. (1990) Proc.Natl. Acad. Sci. USA 87:8447-8451). To date, >1000 disease causingmutations in the CF gene have been identified(http://www.genet.sickkids.on.ca/cftr/). The most prevalent mutation isa deletion of phenylalanine at position 508 of the CFTR amino acidsequence, and is commonly referred to as ΔF508-CFTR. This mutationoccurs in approximately 70% of the cases of cystic fibrosis and isassociated with a severe disease.

The deletion of residue 508 in ΔF508-CFTR prevents the nascent proteinfrom folding correctly. This results in the inability of the mutantprotein to exit the ER, and traffic to the plasma membrane. As a result,the number of channels present in the membrane is far less than observedin cells expressing wild-type CFTR. In addition to impaired trafficking,the mutation results in defective channel gating. Together, the reducednumber of channels in the membrane and the defective gating lead toreduced anion transport across epithelia leading to defective ion andfluid transport. (Quinton, P. M. (1990), FASEB J. 4: 2709-2727). Studieshave shown, however, that the reduced numbers of ΔF508-CFTR in themembrane are functional, albeit less than wild-type CFTR. (Dalemans etal. (1991), Nature Lond. 354: 526-528; Denning et al., supra; Pasyk andFoskett (1995), J. Cell. Biochem. 270: 12347-50). In addition toΔF508-CFTR, other disease causing mutations in CFTR that result indefective trafficking, synthesis, and/or channel gating could be up- ordown-regulated to alter anion secretion and modify disease progressionand/or severity.

Although CFTR transports a variety of molecules in addition to anions,it is clear that this role (the transport of anions) represents oneelement in an important mechanism of transporting ions and water acrossthe epithelium. The other elements include the epithelial Na⁺ channel,ENaC, Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and the basolateralmembrane K⁺ channels, that are responsible for the uptake of chlorideinto the cell.

These elements work together to achieve directional transport across theepithelium via their selective expression and localization within thecell. Chloride absorption takes place by the coordinated activity ofENaC and CFTR present on the apical membrane and the Na⁺—K⁺-ATPase pumpand Cl-channels expressed on the basolateral surface of the cell.Secondary active transport of chloride from the luminal side leads tothe accumulation of intracellular chloride, which can then passivelyleave the cell via Cl⁻ channels, resulting in a vectorial transport.Arrangement of Na⁺/2Cl⁻/K⁺ co-transporter, Na⁺—K⁺-ATPase pump and thebasolateral membrane K⁺ channels on the basolateral surface and CFTR onthe luminal side coordinate the secretion of chloride via CFTR on theluminal side. Because water is probably never actively transporteditself, its flow across epithelia depends on tiny transepithelialosmotic gradients generated by the bulk flow of sodium and chloride.

In addition to cystic fibrosis, modulation of CFTR activity may bebeneficial for other diseases not directly caused by mutations in CFTR,such as secretory diseases and other protein folding diseases mediatedby CFTR. These include, but are not limited to, chronic obstructivepulmonary disease (COPD), dry eye disease, and Sjögren's Syndrome. COPDis characterized by airflow limitation that is progressive and not fullyreversible. The airflow limitation is due to mucus hypersecretion,emphysema, and bronchiolitis. Activators of mutant or wild-type CFTRoffer a potential treatment of mucus hypersecretion and impairedmucociliary clearance that is common in COPD. Specifically, increasinganion secretion across CFTR may facilitate fluid transport into theairway surface liquid to hydrate the mucus and optimized periciliaryfluid viscosity. This would lead to enhanced mucociliary clearance and areduction in the symptoms associated with COPD. Dry eye disease ischaracterized by a decrease in tear aqueous production and abnormal tearfilm lipid, protein and mucin profiles. There are many causes of dryeye, some of which include age, Lasik eye surgery, arthritis,medications, chemical/thermal burns, allergies, and diseases, such ascystic fibrosis and Sjögrens's syndrome. Increasing anion secretion viaCFTR would enhance fluid transport from the corneal endothelial cellsand secretory glands surrounding the eye to increase corneal hydration.This would help to alleviate the symptoms associated with dry eyedisease. Sjögrens's syndrome is an autoimmune disease in which theimmune system attacks moisture-producing glands throughout the body,including the eye, mouth, skin, respiratory tissue, liver, vagina, andgut. Symptoms, include, dry eye, mouth, and vagina, as well as lungdisease. The disease is also associated with rheumatoid arthritis,systemic lupus, systemic sclerosis, and polymypositis/dermatomyositis.Defective protein trafficking is believed to cause the disease, forwhich treatment options are limited. Modulators of CFTR activity mayhydrate the various organs afflicted by the disease and help to elevatethe associated symptoms.

As discussed above, it is believed that the deletion of residue 508 inΔF508-CFTR prevents the nascent protein from folding correctly,resulting in the inability of this mutant protein to exit the ER, andtraffic to the plasma membrane. As a result, insufficient amounts of themature protein are present at the plasma membrane and chloride transportwithin epithelial tissues is significantly reduced. In fact, thiscellular phenomenon of defective ER processing of ABC transporters bythe ER machinery, has been shown to be the underlying basis not only forCF disease, but for a wide range of other isolated and inheriteddiseases. The two ways that the ER machinery can malfunction is eitherby loss of coupling to ER export of the proteins leading to degradation,or by the ER accumulation of these defective/misfolded proteins [AridorM, et al., Nature Med., 5(7), pp 745-751 (1999); Shastry, B. S., et al.,Neurochem. International, 43, pp 1-7 (2003); Rutishauser, J., et al.,Swiss Med Wkly, 132, pp 211-222 (2002); Morello, J P et al., TIPS, 21,pp. 466-469 (2000); Bross P., et al., Human Mut., 14, pp. 186-198(1999)]. The diseases associated with the first class of ER malfunctionare cystic fibrosis (due to misfolded ΔF508-CFTR as discussed above),hereditary emphysema (due to a1-antitrypsin; non Piz variants),hereditary hemochromatosis, hoagulation-fibrinolysis deficiencies, suchas protein C deficiency, Type 1 hereditary angioedema, lipid processingdeficiencies, such as familial hypercholesterolemia, Type 1chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, suchas I-cell disease/pseudo-Hurler, Mucopolysaccharidoses (due to lysosomalprocessing enzymes), Sandhof/Tay-Sachs (due to β-hexosaminidase),Crigler-Najjar type II (due to UDP-glucuronyl-sialyc-transferase),polyendocrinopathy/hyperinsulemia, Diabetes mellitus (due to insulinreceptor), Laron dwarfism (due to growth hormone receptor),myleoperoxidase deficiency, primary hypoparathyroidism (due topreproparathyroid hormone), melanoma (due to tyrosinase). The diseasesassociated with the latter class of ER malfunction are Glycanosis CDGtype 1, hereditary emphysema (due to α1-Antitrypsin (PiZ variant),congenital hyperthyroidism, osteogenesis imperfecta (due to Type I, II,IV procollagen), hereditary hypofibrinogenemia (due to fibrinogen), ACTdeficiency (due to α1-antichymotrypsin), Diabetes insipidus (DI),neurophyseal DI (due to vasopvessin hormone/V2-receptor), neprogenic DI(due to aquaporin II), Charcot-Marie Tooth syndrome (due to peripheralmyelin protein 22), Perlizaeus-Merzbacher disease, neurodegenerativediseases such as Alzheimer's disease (due to PAPP and presenilins),Parkinson's disease, amyotrophic lateral sclerosis, progressivesupranuclear plasy, Pick's disease, several polyglutamine neurologicaldisorders such as Huntington, spinocerebullar ataxia type I, spinal andbulbar muscular atrophy, dentatorubal pallidoluysian, and myotonicdystrophy, as well as spongiform encephalopathies, such as hereditaryCreutzfeldt-Jakob disease (due to prion protein processing defect),Fabry disease (due to lysosomal α-galactosidase A) andStraussler-Scheinker syndrome (due to Prp processing defect).

In addition to up-regulation of CFTR activity, reducing anion secretionby CFTR modulators may be beneficial for the treatment of secretorydiarrheas, in which epithelial water transport is dramatically increasedas a result of secretagogue activated chloride transport. The mechanisminvolves elevation of cAMP and stimulation of CFTR.

Although there are numerous causes of diarrhea, the major consequencesof diarrheal diseases, resulting from excessive chloride transport arecommon to all, and include dehydration, acidosis, impaired growth anddeath.

Acute and chronic diarrheas represent a major medical problem in manyareas of the world. Diarrhea is both a significant factor inmalnutrition and the leading cause of death (5,000,000 deaths/year) inchildren less than five years old.

Secretory diarrheas are also a dangerous condition in patients ofacquired immunodeficiency syndrome (AIDS) and chronic inflammatory boweldisease (IBD). 16 million travelers to developing countries fromindustrialized nations every year develop diarrhea, with the severityand number of cases of diarrhea varying depending on the country andarea of travel.

Diarrhea in barn animals and pets such as cows, pigs and horses, sheep,goats, cats and dogs, also known as scours, is a major cause of death inthese animals. Diarrhea can result from any major transition, such asweaning or physical movement, as well as in response to a variety ofbacterial or viral infections and generally occurs within the first fewhours of the animal's life.

The most common diarrheal causing bacteria is enterotoxogenic E. coli(ETEC) having the K99 pilus antigen. Common viral causes of diarrheainclude rotavirus and coronavirus. Other infectious agents includecryptosporidium, giardia lamblia, and salmonella, among others.

Symptoms of rotaviral infection include excretion of watery feces,dehydration and weakness. Coronavirus causes a more severe illness inthe newborn animals, and has a higher mortality rate than rotaviralinfection. Often, however, a young animal may be infected with more thanone virus or with a combination of viral and bacterial microorganisms atone time. This dramatically increases the severity of the disease.

Accordingly, there is a need for modulators of an ABC transporteractivity, and compositions thereof, that can be used to modulate theactivity of the ABC transporter in the cell membrane of a mammal.

There is a need for methods of treating ABC transporter mediateddiseases using such modulators of ABC transporter activity.

There is a need for methods of modulating an ABC transporter activity inan ex vivo cell membrane of a mammal.

There is a need for modulators of CFTR activity that can be used tomodulate the activity of CFTR in the cell membrane of a mammal.

There is a need for methods of treating CFTR-mediated diseases usingsuch modulators of CFTR activity.

There is a need for methods of modulating CFTR activity in an ex vivocell membrane of a mammal.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, andpharmaceutically acceptable compositions thereof, are useful asmodulators of ABC transporter activity. These compounds have the generalformula I:

or a pharmaceutically acceptable salt thereof, wherein R¹, R², R³, R⁴,R⁵, R⁶, R⁷, and Ar¹ are described generally and in classes andsubclasses below.

These compounds and pharmaceutically acceptable compositions are usefulfor treating or lessening the severity of a variety of diseases,disorders, or conditions, including, but not limited to, cysticfibrosis, Hereditary emphysema, Hereditary hemochromatosis,Coagulation-Fibrinolysis deficiencies, such as Protein C deficiency,Type 1 hereditary angioedema, Lipid processing deficiencies, such asFamilial hypercholesterolemia, Type 1 chylomicronemia,Abetalipoproteinemia, Lysosomal storage diseases, such as I-celldisease/Pseudo-Hurler, Mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, Polyendocrinopathy/Hyperinsulemia, Diabetesmellitus, Laron dwarfism, Myleoperoxidase deficiency, Primaryhypoparathyroidism, Melanoma, Glycanosis CDG type 1, Hereditaryemphysema, Congenital hyperthyroidism, Osteogenesis imperfecta,Hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI),Neurophyseal DI, Neprogenic DI, Charcot-Marie Tooth syndrome,Perlizaeus-Merzbacher disease, neurodegenerative diseases such asAlzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis,Progressive supranuclear plasy, Pick's disease, several polyglutamineneurological disorders such as Huntington, Spinocerebullar ataxia typeI, Spinal and bulbar muscular atrophy, Dentatorubal pallidoluysian, andMyotonic dystrophy, as well as Spongiform encephalopathies, such asHereditary Creutzfeldt-Jakob disease, Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, and Sjogren'sdisease.

DETAILED DESCRIPTION OF THE INVENTION I. General Description ofCompounds of the Invention

The present invention relates to compounds of formula I useful asmodulators of ABC transporter activity:

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein saidring is optionally fused to a 5-12 membered monocyclic or bicyclic,aromatic, partially unsaturated, or saturated ring, wherein each ringcontains 0-4 heteroatoms independently selected from nitrogen, oxygen,or sulfur, wherein Ar¹ has m substituents, each independently selectedfrom —WR_(W);

W is a bond or is an optionally substituted C1-C6 alkylidene chainwherein up to two methylene units of W are optionally and independentlyreplaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—,—NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—;

R^(W) is independently R′, halo, NO₂, CN, CF₃, or OCF₃;

m is 0-5;

each of R¹, R², R³, R⁴, and R⁵ is independently

X is a bond or is an optionally substituted C1-C6 alkylidene chainwherein up to two methylene units of X are optionally and independentlyreplaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—,—NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—;

R^(X) is independently R′, halo, NO₂, CN, CF₃, or OCF₃;

R⁶ is hydrogen, CF₃, —OR′, —SR′, or an optionally substituted C₁₋₆aliphatic group;

R⁷ is hydrogen or a C₁₋₆ aliphatic group optionally substituted with—X—R^(X);

R′ is independently selected from hydrogen or an optionally substitutedgroup selected from a C₁-C₈ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or two occurrences of R′ are taken togetherwith the atom(s) to which they are bound to form an optionallysubstituted 3-12 membered saturated, partially unsaturated, or fullyunsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur.

In certain other embodiments, compounds of formula I are provided:

or a pharmaceutically acceptable salt thereof, wherein:

Ar¹ is a 5-6 membered aromatic monocyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein saidring is optionally fused to a 5-12 membered monocyclic or bicyclic,aromatic, partially unsaturated, or saturated ring, wherein each ringcontains 0-4 heteroatoms independently selected from nitrogen, oxygen,or sulfur, wherein Ar¹ has m substituents each independently selectedfrom —WR^(W);

W is a bond or is an optionally substituted C1-C6 alkylidene chainwherein up to two methylene units of W are optionally and independentlyreplaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—,—NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, —NR′SO₂NR′—;

R^(W) is independently R′, halo, NO₂, CN, CF₃, or OCF₃;

m is 0-5;

each of R¹, R², R³, R⁴, and R⁵ is independently —X—R^(X);

X is a bond or is an optionally substituted C1-C6 alkylidene chainwherein up to two methylene units of X are optionally and independentlyreplaced by —CO—, —CS—, —COCO—, —CONR′—, —CONR′NR′—, —CO₂—, —OCO—,—NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′NR′, —NR′NR′CO—, —NR′CO—, —S—,—SO, —SO₂—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—;

R^(X) is independently R′, halo, NO₂, CN, CF₃, or OCF₃;

R⁶ is hydrogen, CF₃, —OR′, —SR′, or an optionally substituted C₁-C₈aliphatic group;

R⁷ is hydrogen or a C1-C6 aliphatic group optionally substituted with—X—R^(X);

R′ is independently selected from hydrogen or an optionally substitutedgroup selected from a C₁-C₈ aliphatic group, a 3-8-membered saturated,partially unsaturated, or fully unsaturated monocyclic ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur, oran 8-12 membered saturated, partially unsaturated, or fully unsaturatedbicyclic ring system having 0-5 heteroatoms independently selected fromnitrogen, oxygen, or sulfur; or two occurrences of R′ are taken togetherwith the atom(s) to which they are bound to form an optionallysubstituted 3-12 membered saturated, partially unsaturated, or fullyunsaturated monocyclic or bicyclic ring having 0-4 heteroatomsindependently selected from nitrogen, oxygen, or sulfur;

provided that:

i) when R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen, then Ar¹ is notphenyl, 2-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl,2,6-dichlorophenyl, 2,4-dichlorophenyl, 2-bromophenyl, 4-bromophenyl,4-hydroxyphenyl, 2,4-dinitrophenyl, 3,5-dicarboxylic acid phenyl,2,4-dimethylphenyl, 2,6-dimethylphenyl, 2-ethylphenyl,3-nitro-4-methylphenyl, 3-carboxylic-acid phenyl, 2-fluorophenyl,3-fluorophenyl, 3-trifluoromethylphenyl, 3-ethoxyphenyl, 4-chlorophenyl,3-methoxyphenyl, 4-dimethylaminophenyl, 3,4-dimethylphenyl,2-ethylphenyl, or 4-ethoxycarbonylphenyl;

ii) when R¹, R², R³, R⁵, R⁶ and R⁷ are hydrogen, and R⁴ is methoxy, thenAr¹ is not 2-fluorophenyl or 3-fluorophenyl;

iii) when R′, R³, R⁴, R⁵, R⁶ and R⁷ are hydrogen, R² is1,2,3,4-tetrahydroisoquinolin-1-yl-sulfonyl, then Ar¹ is not3-trifluoromethylphenyl;

iv) when R¹, R², R³, R⁴, R⁵ and R⁷ are hydrogen, R⁶ is methyl, then Ar¹is not phenyl;

v) when R¹, R⁴, R⁵, R⁶ and R⁷ are hydrogen, R² and R³, taken together,are methylenedioxy, then Ar¹ is not 4-chlorophenyl, 4-bromophenyl,4-nitrophenyl, 4-carboethoxyphenyl, 6-ethoxy-benzothiazol-2-yl,6-carboethoxy-benzothiazol-2-yl, 6-halo-benzothiazol-2-yl,6-nitro-benzothiazol-2-yl, or 6-thiocyano-benzothiazol-2-yl.

vi) when R¹, R⁴, R⁵, R⁶ and R⁷ are hydrogen, R² and R³, taken together,are methylenedioxy, then Ar¹ is not 4-substituted phenyl wherein saidsubstituent is —SO₂NHR^(xx), wherein R^(xx) is 2-pyridinyl,4-methyl-2-pyrimidinyl, 3,4-dimethyl-5-isoxazolyl;

vii) when R¹, R², R³. R⁴, R⁵, R⁶, and R⁷ are hydrogen, then Ar¹ is notthiazol-2-yl, 1H-1,2,4-triazol-3-yl, or 1H-1,3,4-triazol-2-yl;

viii) when R¹, R², R³, R⁵, R⁶, and R⁷ are hydrogen, and R⁴ is CF₃, OMe,chloro, SCF₃, or OCF₃, then Ar¹ is not 5-methyl-1,2-oxazol-3-yl,thiazol-2-yl, 4-fluorophenyl, pyrimidin-2-yl,1-methyl-1,2-(1H)-pyrazol-5-yl, pyridine-2-yl, phenyl,N-methyl-imidazol-2-yl, imidazol-2-yl, 5-methyl-imidazol-2-yl,1,3-oxazol-2-yl, or 1,3,5-(1H)-triazol-2-yl;

ix) when R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ each is hydrogen, then Ar¹ isnot pyrimidin-2-yl, 4,6-dimethyl-pyrimidin-2-yl,4-methoxy-6-methyl-1,3,5-triazin-2-yl; 5-bromo-pyridin-2-yl,pyridin-2-yl, or 3,5-dichloro-pyridin-2-yl;

x) when R¹, R², R³, R⁴, R⁵ and R⁷ each is hydrogen, R⁶ is hydroxy, thenAr¹ is not 2,6-dichloro-4-aminosulfonyl-phenyl;

xi) when R² or R³ is an optionally substituted N-piperazyl, N-piperidyl,or N-morpholinyl, then Ar¹ is not an optionally substituted ringselected from thiazol-2-yl, pyridyl, phenyl, thiadiazolyl,benzothiazol-2-yl, or indazolyl;

xii) when R² is optionally substituted cyclohexylamino, then Ar¹ is notoptionally substituted phenyl, pyridyl, or thiadiazolyl;

xiii) Ar¹ is not optionally substituted tetrazolyl;

xiv) when R², R⁴, R⁵, R⁶, and R⁷ each is hydrogen, and R¹ and R³ bothare simultaneously CF₃, chloro, methyl, or methoxy, then Ar¹ is not4,5-dihydro-1,3-thiazol-2-yl, thiazol-2-yl, or[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl;

xv) when R¹, R⁴, R⁵, R⁶, and R⁷ each is hydrogen, and Ar¹ isthiazol-2-yl, then neither R² nor R³ is isopropyl, chloro, or CF₃;

xvi) when Ar¹ is 4-methoxyphenyl, 4-trifluoromethylphenyl,2-fluorophenyl, phenyl, or 3-chlorophenyl, then:

-   -   a) when R¹, R², R⁴, R⁵, R⁶, and R⁷ each is hydrogen, then R³ is        not methoxy; or    -   b) when R¹, R³, R⁴, R⁵, R⁶, and R⁷ each is hydrogen, then R² is        not chloro; or    -   c) when R¹, R², R³, R⁵, R⁶, and R⁷ each is hydrogen, then R⁴ is        not methoxy; or    -   d) when when R¹, R³, R⁴, R⁶, and R⁷ each is hydrogen, and R⁵ is        ethyl, then R² is not chloro;    -   e) when R¹, R², R⁴, R⁵, R⁶, and R⁷ each is hydrogen, then R³ is        not chloro;

xvi) when R¹, R³, R⁴, R⁵, R⁶, and R⁷ each is hydrogen, and R² is CF₃ orOCF₃, then Ar¹ is not [3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl;

xvii) when R¹, R², R⁴, R⁵, R⁶, and R⁷ each is hydrogen, and R³ ishydrogen or CF₃, then Ar¹ is not a phenyl substituted with —OCH₂CH₂Ph,—OCH₂CH₂(2-trifluoromethyl-phenyl),—OCH₂CH₂-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl), orsubstituted 1H-pyrazol-3-yl; and

xviii) the following two compounds are excluded:

2. Compounds and Definitions

Compounds of this invention include those described generally above, andare further illustrated by the classes, subclasses, and speciesdisclosed herein. As used herein, the following definitions shall applyunless otherwise indicated.

The term “ABC-transporter” as used herein means an ABC-transporterprotein or a fragment thereof comprising at least one binding domain,wherein said protein or fragment thereof is present in vivo or in vitro.The term “binding domain” as used herein means a domain on theABC-transporter that can bind to a modulator. See, e.g., Hwang, T. C. etal., J. Gen. Physiol. (1998): 111(3), 477-90.

The term “CFTR” as used herein means cystic fibrosis transmembraneconductance regulator or a mutation thereof capable of regulatoractivity, including, but not limited to, ΔF508 CFTR and G55 ID CFTR(see, e.g., http://www.genet.sickkids.on.ca/cftr/, for CFTR mutations).

The term “modulating” as used herein means increasing or decreasing by ameasurable amount.

For purposes of this invention, the chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, generalprinciples of organic chemistry are described in “Organic Chemistry”,Thomas Sorrell, University Science Books, Sausalito: 1999, and “March'sAdvanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March,J., John Wiley & Sons, New York: 2001, the entire contents of which arehereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted”,whether preceded by the term “optionally” or not, refers to thereplacement of hydrogen radicals in a given structure with the radicalof a specified substituent. Unless otherwise indicated, an optionallysubstituted group may have a substituent at each substitutable positionof the group, and when more than one position in any given structure maybe substituted with more than one substituent selected from a specifiedgroup, the substituent may be either the same or different at everyposition. Combinations of substituents envisioned by this invention arepreferably those that result in the formation of stable or chemicallyfeasible compounds. The term “stable”, as used herein, refers tocompounds that are not substantially altered when subjected toconditions to allow for their production, detection, and preferablytheir recovery, purification, and use for one or more of the purposesdisclosed herein. In some embodiments, a stable compound or chemicallyfeasible compound is one that is not substantially altered when kept ata temperature of 40° C. or less, in the absence of moisture or otherchemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated or thatcontains one or more units of unsaturation, or a monocyclic hydrocarbonor bicyclic hydrocarbon that is completely saturated or that containsone or more units of unsaturation, but which is not aromatic (alsoreferred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”),that has a single point of attachment to the rest of the molecule.Unless otherwise specified, aliphatic groups contain 1-20 aliphaticcarbon atoms. In some embodiments, aliphatic groups contain 1-10aliphatic carbon atoms. In other embodiments, aliphatic groups contain1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groupscontain 1-6 aliphatic carbon atoms, and in yet other embodimentsaliphatic groups contain 1-4 aliphatic carbon atoms. In someembodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refersto a monocyclic C₃-C₈ hydrocarbon or bicyclic or tricyclic C₉-C₁₄hydrocarbon that is completely saturated or that contains one or moreunits of unsaturation, but which is not aromatic, that has a singlepoint of attachment to the rest of the molecule wherein any individualring in said bicyclic ring system has 3-7 members. Suitable aliphaticgroups include, but are not limited to, linear or branched, substitutedor unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof suchas (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.Suitable cycloaliphatic groups include cycloalkyl, bicyclic cycloalkyl(e.g., decalin), bridged bicycloalkyl such as norbornyl or[2.2.2]bicyclo-octyl, or bridged tricyclic such as adamantyl.

The term “heteroaliphatic”, as used herein, means aliphatic groupswherein one or two carbon atoms are independently replaced by one ormore of oxygen, sulfur, nitrogen, phosphorus, or silicon.Heteroaliphatic groups may be substituted or unsubstituted, branched orunbranched, cyclic or acyclic, and include “heterocycle”,“heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or“heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic,or tricyclic ring systems in which one or more ring members is anindependently selected heteroatom. In some embodiments, the“heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic”group has three to fourteen ring members in which one or more ringmembers is a heteroatom independently selected from oxygen, sulfur,nitrogen, or phosphorus, and each ring in the system contains 3 to 7ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon (including, any oxidized form of nitrogen,sulfur, phosphorus, or silicon; the quaternized form of any basicnitrogen or; a substitutable nitrogen of a heterocyclic ring, forexample N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) orNR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloaliphatic” and “haloalkoxy” means aliphatic or alkoxy, asthe case may be, substituted with one or more halo atoms. The term“halogen” or “halo” means F, Cl, Br, or I. Examples of haloaliphaticinclude —CHF₂, —CH₂F, —CF₃, —CF₂—, or perhaloalkyl, such as, —CF₂CF₃.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic,bicyclic, and tricyclic ring systems having a total of five to fourteenring members, wherein at least one ring in the system is aromatic andwherein each ring in the system contains 3 to 7 ring members. The term“aryl” may be used interchangeably with the term “aryl ring”. The term“aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in“heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic,and tricyclic ring systems having a total of five to fourteen ringmembers, wherein at least one ring in the system is aromatic, at leastone ring in the system contains one or more heteroatoms, and whereineach ring in the system contains 3 to 7 ring members. The term“heteroaryl” may be used interchangeably with the term “heteroaryl ring”or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) orheteroaryl (including heteroaralkyl and heteroarylalkoxy and the like)group may contain one or more substituents. Suitable substituents on theunsaturated carbon atom of an aryl or heteroaryl group are selected fromhalo; —R^(o); —OR^(o); —SR^(o); 1,2-methylene-dioxy; 1,2-ethylenedioxy;phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionallysubstituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted withR^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN;—N(R^(o))₂; —NR′C(O)R^(o); —NR′C(O)N(R^(o))₂; —NR′CO₂R^(o);—NR′NR′C(O)R^(o); —NR′NR′C(O)N(R^(o))₂; —NR′NR′CO₂R^(o); —C(O)C(O)R^(o);—C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(O)N(R^(o))₂;—OC(O)N(R^(o))₂; —S(O)₂R^(o); —SO₂N(R^(o))₂; —S(O)R^(o);—NR′SO₂N(R^(o))₂; —NR′SO₂R^(o); —C(═S)N(R^(o))₂; —C(═NH)—N(R^(o))₂; or—(CH₂)₀₋₂NHC(O)R^(o) wherein each independent occurrence of R^(o) isselected from hydrogen, optionally substituted C₁₋₆ aliphatic, anunsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl,—O(Ph), or —CH₂(Ph), or, notwithstanding the definition above, twoindependent occurrences of R^(o), on the same substituent or differentsubstituents, taken together with the atom(s) to which each R^(o) groupis bound, form a 3-8-membered cycloalkyl, heterocyclyl, aryl, orheteroaryl ring having 0-3 heteroatoms independently selected fromnitrogen, oxygen, or sulfur. Optional substituents on the aliphaticgroup of R′ are selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂,halo, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H,CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, whereineach of the foregoing C₁₋₄aliphatic groups of R′ is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclicring may contain one or more substituents. Suitable substituents on thesaturated carbon of an aliphatic or heteroaliphatic group, or of anon-aromatic heterocyclic ring are selected from those listed above forthe unsaturated carbon of an aryl or heteroaryl group and additionallyinclude the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*,═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independentlyselected from hydrogen or an optionally substituted C₁₋₆ aliphatic.Optional substituents on the aliphatic group of R* are selected fromNH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halo, C₁₋₄ aliphatic, OH,O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄ aliphatic), O(halo C₁₋₄aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoingC₁₋₄aliphatic groups of R* is unsubstituted.

Optional substituents on the nitrogen of a non-aromatic heterocyclicring are selected from —R′, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺,—C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺)₂, —C(═NH)—N(R⁺)₂, or—NR+SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆aliphatic, optionally substituted phenyl, optionally substituted —O(Ph),optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph);optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 memberedheteroaryl or heterocyclic ring having one to four heteroatomsindependently selected from oxygen, nitrogen, or sulfur, or,notwithstanding the definition above, two independent occurrences of R⁺,on the same substituent or different substituents, taken together withthe atom(s) to which each R⁺ group is bound, form a 3-8-memberedcycloalkyl, heterocyclyl, aryl, or heteroaryl ring having 0-3heteroatoms independently selected from nitrogen, oxygen, or sulfur.Optional substituents on the aliphatic group or the phenyl ring of R⁺are selected from NH₂, NH(C₁₋₄ aliphatic), N(C₁₋₄ aliphatic)₂, halo,C₁₋₄ aliphatic, OH, O(C₁₋₄ aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), whereineach of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbonchain that may be fully saturated or have one or more units ofunsaturation and has two points of attachment to the rest of themolecule. The term “spirocycloalkylidene” refers to a carbocyclic ringthat may be fully saturated or have one or more units of unsaturationand has two points of attachment from the same ring carbon atom to therest of the molecule.

As detailed above, in some embodiments, two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein), are takentogether together with the atom(s) to which each variable is bound toform a 3-8-membered cycloalkyl, heterocyclyl, aryl, or heteroaryl ringhaving 0-3 heteroatoms independently selected from nitrogen, oxygen, orsulfur. Exemplary rings that are formed when two independent occurrencesof R^(o) (or R⁺, or any other variable similarly defined herein) aretaken together with the atom(s) to which each variable is bound include,but are not limited to the following: a) two independent occurrences ofR^(o) (or R⁺, or any other variable similarly defined herein) that arebound to the same atom and are taken together with that atom to form aring, for example, N(R^(o))₂, where both occurrences of R^(o) are takentogether with the nitrogen atom to form a piperidin-1-yl,piperazin-1-yl, or morpholin-4-yl group; and b) two independentoccurrences of R^(o) (or R⁺, or any other variable similarly definedherein) that are bound to different atoms and are taken together withboth of those atoms to form a ring, for example where a phenyl group issubstituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atomsto which they are bound to form a fused 6-membered oxygen containingring:

It will be appreciated that a variety of other rings can be formed whentwo independent occurrences of R^(o) (or R⁺, or any other variablesimilarly defined herein) are taken together with the atom(s) to whicheach variable is bound and that the examples detailed above are notintended to be limiting.

A substituent bond in, e.g., a bicyclic ring system, as shown below,means that the substituent can be attached to any substitutable ringatom on either ring of the bicyclic ring system:

Unless otherwise stated, structures depicted herein are also meant toinclude all isomeric (e.g., enantiomeric, diastereomeric, and geometric(or conformational)) forms of the structure; for example, the R and Sconfigurations for each asymmetric center, (Z) and (E) double bondisomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Unless otherwise stated, alltautomeric forms of the compounds of the invention are within the scopeof the invention. E.g., when R⁵ in compounds of formula I is hydrogen,compounds of formula I may exist as tautomers:

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ¹³C— or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

3. Description of Exemplary Compounds

In some embodiments of the present invention, Ar¹ is selected from:

wherein ring A₁ 5-6 membered aromatic monocyclic ring having 0-4heteroatoms independently selected from nitrogen, oxygen, or sulfur; or

A₁ and A₂, together, is an 8-14 aromatic, bicyclic or tricyclic arylring, wherein each ring contains 0-4 heteroatoms independently selectedfrom nitrogen, oxygen, or sulfur.

In some embodiments, A₁ is an optionally substituted 6 membered aromaticring having 0-4 heteroatoms, wherein said heteroatom is nitrogen. Insome embodiments, A₁ is an optionally substituted phenyl. Or, A₁ is anoptionally substituted pyridyl, pyrimidinyl, pyrazinyl or triazinyl. Or,A₁ is an optionally substituted pyrazinyl or triazinyl. Or, A₁ is anoptionally substituted pyridyl.

In some embodiments, A₁ is an optionally substituted 5-membered aromaticring having 0-3 heteroatoms, wherein said heteroatom is nitrogen,oxygen, or sulfur. In some embodiments, A₁ is an optionally substituted5-membered aromatic ring having 1-2 nitrogen atoms. In one embodiment,A₁ is an optionally substituted 5-membered aromatic ring other thanthiazolyl.

In some embodiments, A₂ is an optionally substituted 6 membered aromaticring having 0-4 heteroatoms, wherein said heteroatom is nitrogen. Insome embodiments, A₂ is an optionally substituted phenyl. Or, A₂ is anoptionally substituted pyridyl, pyrimidinyl, pyrazinyl, or triazinyl.

In some embodiments, A₂ is an optionally substituted 5-membered aromaticring having 0-3 heteroatoms, wherein said heteroatom is nitrogen,oxygen, or sulfur. In some embodiments, A₂ is an optionally substituted5-membered aromatic ring having 1-2 nitrogen atoms. In certainembodiments, A₂ is an optionally substituted pyrrolyl.

In some embodiments, A₂ is an optionally substituted 5-7 memberedsaturated or unsaturated heterocyclic ring having 1-3 heteroatomsindependently selected from nitrogen, sulfur, or oxygen. Exemplary suchrings include piperidyl, piperazyl, morpholinyl, thiomorpholinyl,pyrrolidinyl, tetrahydrofuranyl, etc.

In some embodiments, A₂ is an optionally substituted 5-10 memberedsaturated or unsaturated carbocyclic ring. In one embodiment, A₂ is anoptionally substituted 5-10 membered saturated carbocyclic ring.Exemplary such rings include cyclohexyl, cyclopentyl, etc.

In some embodiments, ring A₂ is selected from:

wherein ring A₂ is fused to ring A₁ through two adjacent ring atoms.

In other embodiments, W is a bond or is an optionally substituted C₁₋₆alkylidene chain wherein one or two methylene units are optionally andindependently replaced by O, NR′, S, SO, SO₂, or COO, CO, SO₂NR′,NR′SO₂, C(O)NR′, NR′C(O), OC(O), OC(O)NR′, and R^(W) is R′ or halo. Instill other embodiments, each occurrence of WR^(W) is independently—C₁-C₃ alkyl, C₁-C₃ perhaloalkyl, —O(C₁-C₃alkyl), —CF₃, —OCF₃, —SCF₃,—F, —Cl, —Br, or —COOR′, —COR′, —O(CH₂)₂N(R′)(R′), —O(CH₂)N(R′)(R′),—CON(R′)(R′), —(CH₂)₂OR′, —(CH₂)OR′, optionally substituted monocyclicor bicyclic aromatic ring, optionally substituted arylsulfone,optionally substituted 5-membered heteroaryl ring, —N(R′)(R′),—(CH₂)₂N(R′)(R′), or —(CH₂)N(R′)(R′).

In some embodiments, m is 0. Or, m is 1. Or, m is 2. In someembodiments, m is 3. In yet other embodiments, m is 4.

In one embodiment, R⁵ is X—R^(X). In some embodiments R⁵ is hydrogen.Or, R⁵ is an optionally substituted C₁₈ aliphatic group. In someembodiments, R⁵ is optionally substituted C₁₋₄ aliphatic. Or, R⁵ isbenzyl.

In some embodiments R⁶ is hydrogen. Or, R⁶ is an optionally substitutedC₁₈ aliphatic group. In some embodiments, R⁶ is optionally substitutedC₁₋₄ aliphatic. In certain other embodiments, R⁶ is —(O—C₁₋₄ aliphatic)or —(S—C₁₋₄ aliphatic). Preferably, R⁶ is —OMe or —SMe. In certain otherembodiments, R⁶ is CF₃.

In one embodiment of the present invention, R¹, R², R³, and R⁴ aresimultaneously hydrogen. In another embodiment, R⁶ and R⁷ are bothsimultaneously hydrogen.

In another embodiment of the present invention, R¹, R², R³, R⁴, and R⁵are simultaneously hydrogen. In another embodiment of the presentinvention, R¹, R², R³, R⁴, R⁵ and R⁶ are simultaneously hydrogen.

In another embodiment of the present invention, R² is X—R^(X), wherein Xis —SO₂NR′—, and R^(X) is R′; i.e., R² is —SO₂N(R′)₂. In one embodiment,the two R′ therein taken together form an optionally substituted 5-7membered ring with 0-3 additional heteroatoms selected from nitrogen,oxygen, or sulfur. Or, R¹, R³, R⁴, R⁵ and R⁶ are simultaneouslyhydrogen, and R² is SO₂N(R′)₂.

In some embodiments, X is a bond or is an optionally substituted C₁₋₆alkylidene chain wherein one or two non-adjacent methylene units areoptionally and independently replaced by O, NR′, S, SO₂, or COO, CO, andR^(X) is R′ or halo. In still other embodiments, each occurrence ofXR^(X) is independently —C₁₋₃alkyl, —O(C₁₋₃alkyl), —CF₃, —OCF₃, —SCF₃,—F, —Cl, —Br, OH, —COOR′, —COR′, —O(CH₂)₂N(R′)(R′), —O(CH₂)N(R′)(R′),—CON(R′)(R′), —(CH₂)₂OR′, —(CH₂)OR′, optionally substituted phenyl,—N(R′)(R′), —(CH₂)₂N(R′)(R′), or —(CH₂)N(R′)(R′).

In some embodiments, R⁷ is hydrogen. In certain other embodiment, R⁷ isC₁₋₄ straight or branched aliphatic.

In some embodiments, R^(W) is selected from halo, cyano, CF₃, CHF₂,OCHF₂, Me, Et, CH(Me)₂, CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh,O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl,SMe, SCF₃, SCHF₂, SEt, CH₂CN, NH₂, NHMe, N(Me)₂, NHEt, N(Et)₂, C(O)CH₃,C(O)Ph, C(O)NH₂, SPh, SO₂— (amino-pyridyl), SO₂NH₂, SO₂Ph, SO₂NHPh,SO₂—N-morpholino, SO₂—N-pyrrolidyl, N-pyrrolyl, N-morpholino,1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl,4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2-yl, furan-2-yl,4-methyl-4H-[1,2,4]triazol-3-yl,3-(4′-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph,NHSO₂Me, 2-indolyl, 5-indolyl, —CH₂CH₂OH, —OCF₃, O-(2,3-dimethylphenyl),5-methylfuryl, —SO₂—N-piperidyl, 2-tolyl, 3-tolyl, 4-tolyl, O-butyl,NHCO₂C(Me)₃, CO₂C(Me)₃, isopropenyl, n-butyl, O-(2,4-dichlorophenyl),NHSO₂PhMe, O-(3-chloro-5-trifluoromethyl-2-pyridyl),phenylhydroxymethyl, 2,5-dimethylpyrrolyl, NHCOCH₂C(Me)₃,O-(2-tert-butyl)phenyl, 2,3-dimethylphenyl, 3,4-dimethylphenyl,4-hydroxymethyl phenyl, 4-dimethylaminophenyl, 2-trifluoromethylphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-cyanomethylphenyl,4-isobutylphenyl, 3-pyridyl, 4-pyridyl, 4-isopropylphenyl,3-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3,4-methylenedioxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl,4-ethoxyphenyl, 2-methylthiophenyl, 4-methylthiophenyl,2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl,3,4-dimethoxyphenyl, 5-chloro-2-methoxyphenyl, 2-OCF₃-phenyl,3-trifluoromethoxy-phenyl, 4-trifluoromethoxyphenyl, 2-phenoxyphenyl,4-phenoxyphenyl, 2-fluoro-3-methoxy-phenyl, 2,4-dimethoxy-5-pyrimidyl,5-isopropyl-2-methoxyphenyl, 2-fluorophenyl, 3-fluorophenyl,4-fluorophenyl, 3-cyanophenyl, 3-chlorophenyl, 4-chlorophenyl,2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl,3,4-difluorophenyl, 3,5-difluorophenyl, 3-chloro-4-fluoro-phenyl,3,5-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl,3,4-dichlorophenyl, 2,4-dichlorophenyl, 3-methoxycarbonylphenyl,4-methoxycarbonyl phenyl, 3-isopropyloxycarbonylphenyl,3-acetamidophenyl, 4-fluoro-3-methylphenyl, 4-methanesulfinyl-phenyl,4-methanesulfonyl-phenyl, 4-N-(2-N,N-dimethylaminoethyl)carbamoylphenyl,5-acetyl-2-thienyl, 2-benzothienyl, 3-benzothienyl, furan-3-yl,4-methyl-2-thienyl, 5-cyano-2-thienyl, N′-phenylcarbonyl-N-piperazinyl,—NHCO₂Et, —NHCO₂Me, N-pyrrolidinyl, —NHSO₂(CH₂)₂ N-piperidine,—NHSO₂(CH₂)₂ N-morpholine, —NHSO₂(CH₂)₂N(Me)₂, COCH₂N(Me)COCH₂NHMe,—CO₂Et, O-propyl, —CH₂CH₂NHCO₂C(Me)₃, hydroxy, aminomethyl, pentyl,adamantyl, cyclopentyl, ethoxyethyl, C(Me)₂CH₂OH, C(Me)₂CO₂Et, —CHOHMe,CH₂CO₂Et, —C(Me)₂CH₂NHCO₂C(Me)₃, O(CH₂)₂OEt, O(CH₂)₂OH, CO₂Me,hydroxymethyl, 1-methyl-1-cyclohexyl, 1-methyl-1-cyclooctyl,1-methyl-1-cycloheptyl, C(Et)₂C(Me)₃, C(Et)₃, CONHCH₂CH(Me)₂,2-aminomethyl-phenyl, ethenyl, 1-piperidinylcarbonyl, ethynyl,cyclohexyl, 4-methylpiperidinyl, —OCO₂Me, —C(Me)₂CH₂NHCO₂CH₂CH(Me)₂,—C(Me)₂CH₂NHCO₂CH₂CH₂CH₃, —C(Me)₂CH₂NHCO₂Et, —C(Me)₂CH₂NHCO₂Me,—C(Me)₂CH₂NHCO₂CH₂C(Me)₃, —CH₂NHCOCF₃, —CH₂NHCO₂C(Me)₃,—C(Me)₂CH₂NHCO₂(CH₂)₃CH₃, C(Me)₂CH₂NHCO₂(CH₂)₂OMe, C(OH)(CF₃)₂,—C(Me)₂CH₂NHCO₂CH₂-tetrahydrofurane-3-yl, C(Me)₂CH₂—O—(CH₂)₂OMe, or3-ethyl-2,6-dioxopiperidin-3-yl.

In one embodiment, R′ is hydrogen.

In one embodiment, R′ is a C1-C8 aliphatic group, optionally substitutedwith up to 3 substituents selected from halo, CN, CF₃, CHF₂, OCF₃, orOCHF₂, wherein up to two methylene units of said C1-C8 aliphatic isoptionally replaced with —CO—, —CONH(C1-C4 alkyl)-, —CO₂—, —OCO—,—N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4 alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4alkyl)-, —N(C1-C4 alkyl)CO—, —S—, —N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-,N(C1-C4 alkyl)SO₂—, or —N(C1-C4 alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, R′ is a 3-8 membered saturated, partiallyunsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatomsindependently selected from nitrogen, oxygen, or sulfur, wherein R′ isoptionally substituted with up to 3 substituents selected from halo, CN,CF₃, CHF₂, OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to two methyleneunits of said C1-C6 alkyl is optionally replaced with —CO—, —CONH(C1-C4alkyl)-, —CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—,—N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, R′ is an 8-12 membered saturated, partiallyunsaturated, or fully unsaturated bicyclic ring system having 0-5heteroatoms independently selected from nitrogen, oxygen, or sulfur;wherein R′ is optionally substituted with up to 3 substituents selectedfrom halo, CN, CF₃, CHF₂, OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to twomethylene units of said C1-C6 alkyl is optionally replaced with —CO—,—CONH(C1-C4 alkyl)-, —CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4alkyl)CON(C1-C4 alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—,—N(C1-C4 alkyl)-, —SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4alkyl)SO₂N(C1-C4 alkyl)-.

In one embodiment, two occurrences of R′ are taken together with theatom(s) to which they are bound to form an optionally substituted 3-12membered saturated, partially unsaturated, or fully unsaturatedmonocyclic or bicyclic ring having 0-4 heteroatoms independentlyselected from nitrogen, oxygen, or sulfur, wherein R′ is optionallysubstituted with up to 3 substituents selected from halo, CN, CF₃, CHF₂,OCF₃, OCHF₂, or C1-C6 alkyl, wherein up to two methylene units of saidC1-C6 alkyl is optionally replaced with —CO—, —CONH(C1-C4 alkyl)-,—CO₂—, —OCO—, —N(C1-C4 alkyl)CO₂—, —O—, —N(C1-C4 alkyl)CON(C1-C4alkyl)-, —OCON(C1-C4 alkyl)-, —N(C1-C4 alkyl)CO—, —S—, —N(C1-C4 alkyl)-,—SO₂N(C1-C4 alkyl)-, N(C1-C4 alkyl)SO₂—, or —N(C1-C4 alkyl)SO₂N(C1-C4alkyl)-.

According to one embodiment, the present invention provides compounds offormula IIA or formula IIB:

According to another embodiment, the present invention providescompounds of formula IIIA, formula IIIB, formula IIIC, formula IIID, orformula IIIE:

wherein each of X₁, X₂, X₃, X₄, and X₅ is independently selected from CHor N; and X₆ is O, S, or NR′.

In one embodiment, compounds of formula IIIA, formula IIIB, formulaIIIC, formula IIID, or formula IIIE have y occurrences of substituentX—R^(X), wherein y is 0-4. Or, y is 1. Or, y is 2.

In some embodiments of formula IIIA, X₁, X₂, X₃, X₄, and X₅ takentogether with WR^(W) and m is optionally substituted phenyl.

In some embodiments of formula IIIA, X₁, X₂, X₃, X₄, and X₅ takentogether is an optionally substituted ring selected from:

In some embodiments of formula IIIB, formula IIIC, formula IIID, orformula IIIE, X₁, X₂, X₃, X₄, X₅, or X₆, taken together with ring A₂ isan optionally substituted ring selected from:

In some embodiments, R^(W) is selected from halo, cyano, CF₃, CHF₂,OCHF₂, Me, Et, CH(Me)₂, CHMeEt, n-propyl, t-butyl, OMe, OEt, OPh,O-fluorophenyl, O-difluorophenyl, O-methoxyphenyl, O-tolyl, O-benzyl,SMe, SCF₃, SCHF₂, SEt, CH₂CN, NH₂, NHMe, N(Me)₂, NHEt, N(Et)₂, C(O)CH₃,C(O)Ph, C(O)NH₂, SPh, SO₂— (amino-pyridyl), SO₂NH₂, SO₂Ph, SO₂NHPh,SO₂—N-morpholino, SO₂—N-pyrrolidyl, N-pyrrolyl, N-morpholino,1-piperidyl, phenyl, benzyl, (cyclohexyl-methylamino)methyl,4-Methyl-2,4-dihydro-pyrazol-3-one-2-yl, benzimidazol-2-yl, furan-2-yl,4-methyl-4H-[1,2,4]triazol-3-yl,3-(4′-chlorophenyl)-[1,2,4]oxadiazol-5-yl, NHC(O)Me, NHC(O)Et, NHC(O)Ph,or NHSO₂Me

In some embodiments, X and R^(X), taken together, is Me, Et, halo, CN,CF₃, OH, OMe, OEt, SO₂N(Me)(fluorophenyl), SO₂-(4-methyl-piperidin-1-yl,or SO₂—N-pyrrolidinyl.

According to another embodiment, the present invention providescompounds of formula IVA, formula IVB, or formula IVC:

In one embodiment compounds of formula IVA, formula IVB, and formula IVChave y occurrences of substituent X—R^(X), wherein y is 0-4. Or, y is 1.Or, y is 2.

In one embodiment, the present invention provides compounds of formulaIVA, formula IVB, and formula IVC, wherein X is a bond and R^(X) ishydrogen.

In one embodiment, the present invention provides compounds of formulaformula IVB, and formula IVC, wherein ring A₂ is an optionallysubstituted, saturated, unsaturated, or aromatic seven membered ringwith 0-3 heteroatoms selected from O, S, or N. Exemplary rings includeazepanyl, 5,5-dimethyl azepanyl, etc.

In one embodiment, the present invention provides compounds of formulaIVB and IVC, wherein ring A₂ is an optionally substituted, saturated,unsaturated, or aromatic six membered ring with 0-3 heteroatoms selectedfrom O, S, or N. Exemplary rings include piperidinyl,4,4-dimethylpiperidinyl, etc.

In one embodiment, the present invention provides compounds of formulaIVB and IVC, wherein ring A₂ is an optionally substituted, saturated,unsaturated, or aromatic five membered ring with 0-3 heteroatomsselected from O, S, or N.

In one embodiment, the present invention provides compounds of formulaIVB and IVC, wherein ring A₂ is an optionally substituted five memberedring with one nitrogen atom, e.g., pyrrolyl or pyrrolidinyl.

According to one embodiment of formula IVA, the following compound offormula VA-1 is provided:

wherein each of WR^(W2) and WR^(W4) is independently selected fromhydrogen, CN, CF₃, halo, C1-C6 straight or branched alkyl, 3-12 memberedcycloaliphatic, phenyl, C5-C10 heteroaryl or C3-C7 heterocyclic, whereinsaid heteroaryl or heterocyclic has up to 3 heteroatoms selected from O,S, or N, wherein said WR^(W2) and WR^(W4) is independently andoptionally substituted with up to three substituents selected from —OR′,—CF₃, —OCF₃, SR′, S(O)R′, SO₂R′, —SCF₃, halo, CN, —COOR′, —COR′,—O(CH₂)₂N(R′)(R′), —O(CH₂)N(R′)(R′), —CON(R′)(R′), —(CH₂)₂OR′,—(CH₂)OR′, CH₂CN, optionally substituted phenyl or phenoxy, —N(R′)(R′),—NR′C(O)OR′, —NR′C(O)R′, —(CH₂)₂N(R′)(R′), or —(CH₂)N(R′)(R′); and

WR^(W5) is selected from hydrogen, —OH, NH₂, CN, CHF₂, NHR′, N(R′)₂,—NHC(O)R′, —NHC(O)OR′, NHSO₂R′, —OR′, CH₂OH, CH₂N(R′)₂, C(O)OR′,SO₂NHR′, SO₂N(R′)₂, or CH₂NHC(O)OR′. Or, WR^(W4) and WR^(W5) takentogether form a 5-7 membered ring containing 0-3 three heteroatomsselected from N, O, or S, wherein said ring is optionally substitutedwith up to three WR^(W) substituents.

In one embodiment, compounds of formula VA-1 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0.

In one embodiment, the present invention provides compounds of formulaVA-1, wherein X is a bond and R^(X) is hydrogen.

In one embodiment, the present invention provides compounds of formulaVA-1, wherein:

each of WR^(W2) and WR^(W4) is independently selected from hydrogen, CN,CF₃, halo, C1-C6 straight or branched alkyl, 3-12 memberedcycloaliphatic, or phenyl, wherein said WR^(W2) and WR^(W4) isindependently and optionally substituted with up to three substituentsselected from —OR′, —CF₃, —OCF₃, —SCF₃, halo, —COOR′, —COR′,—O(CH₂)₂N(R′)(R′), —O(CH₂)N(R′)(R′), —CON(R′)(R′), —(CH₂)₂OR′,—(CH₂)OR′, optionally substituted phenyl, —N(R′)(R′), —NC(O)OR′,—NC(O)R′, —(CH₂)₂N(R′)(R′), or —(CH₂)N(R′)(R′); and

WR^(W5) is selected from hydrogen, —OH, NH₂, CN, NHR′, N(R′)₂,—NHC(O)R′, —NHC(O)OR′, NHSO₂R′, —OR′, CH₂OH, C(O)OR′, SO₂NHR′, orCH₂NHC(O)O—(R′).

In one embodiment, the present invention provides compounds of formulaVA-1, wherein:

WR^(W2) is a phenyl ring optionally substituted with up to threesubstituents selected from —OR′, —CF₃, —OCF₃, SR′, S(O)R′, SO₂R′, —SCF₃,halo, CN, —COOR′, —COR′, —O(CH₂)₂N(R′)(R′), —O(CH₂)N(R′)(R′),—CON(R′)(R′), —(CH₂)₂OR′, —(CH₂)OR′, CH₂CN, optionally substitutedphenyl or phenoxy, —N(R′)(R′), —NR′C(O)OR′, —NR′C(O)R′,—(CH₂)₂N(R′)(R′), or —(CH₂)N(R′)(R′);

WR^(W4) is C1-C6 straight or branched alkyl; and

WR^(W5) is OH.

In one embodiment, each of WR^(W2) and WR^(W4) is independently selectedfrom CF₃ or halo. In one embodiment, each of WR^(W2) and WR^(W4) isindependently selected from optionally substituted hydrogen, C1-C6straight or branched alkyl. In certain embodiments, each of WR^(W2) andWR^(W4) is independently selected from optionally substituted n-propyl,isopropyl, n-butyl, sec-butyl, t-butyl, 1,1-dimethyl-2-hydroxyethyl,1,1-dimethyl-2-(ethoxycarbonyl)-ethyl,1,1-dimethyl-3-(t-butoxycarbonyl-amino) propyl, or n-pentyl.

In one embodiment, each of WR^(W2) and WR^(W4) is independently selectedfrom optionally substituted 3-12 membered cycloaliphatic. Exemplaryembodiments of such cycloaliphatic include cyclopentyl, cyclohexyl,cycloheptyl, norbornyl, adamantyl, [2.2.2.]bicyclo-octyl,[2.3.1.]bicyclo-octyl, or [3.3.1]bicyclo-nonyl.

In certain embodiments WR^(W2) is hydrogen and WR^(W4) is C1-C6 straightor branched alkyl. In certain embodiments, WR^(W4) is selected frommethyl, ethyl, propyl, n-butyl, sec-butyl, or t-butyl.

In certain embodiments WR^(W4) is hydrogen and WR^(W2) is C1-C6 straightor branched alkyl. In certain embodiments, WR^(W2) is selected frommethyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, or n-pentyl.

In certain embodiments each of WR^(W2) and WR^(W4) is C1-C6 straight orbranched alkyl. In certain embodiments, each of WR^(W2) and WR^(W4) isselected from methyl, ethyl, propyl, n-butyl, sec-butyl, t-butyl, orpentyl.

In one embodiment, WR^(W5) is selected from hydrogen, CHF₂, NH₂, CN,NHR′, N(R′)₂, CH₂N(R′)₂, —NHC(O)R′, —NHC(O)OR′, —OR′, C(O)OR′, orSO₂NHR′. Or, WR^(W5) is —OR′, e.g., OH.

In certain embodiments, WR^(W5) is selected from hydrogen, NH₂, CN,CHF₂, NH(C1-C6 alkyl), N(C1-C6 alkyl)₂, —NHC(O)(C1-C6 alkyl),—CH₂NHC(O)O(C1-C6 alkyl), —NHC(O)O(C1-C6 alkyl), —OH, —O(C1-C6 alkyl),C(O)O(C1-C6 alkyl), CH₂O(C1-C6 alkyl), or SO₂NH₂. In another embodiment,WR^(W5) is selected from —OH, OMe, NH₂, —NHMe, —N(Me)₂, —CH₂NH₂, CH₂OH,NHC(O)OMe, NHC(O)OEt, CN, CHF₂, —CH₂NHC(O)O(t-butyl), —O-(ethoxyethyl),—O-(hydroxyethyl), —C(O)OMe, or —SO₂NH₂.

In one embodiment, compound of formula VA-1 has one, preferably more, ormore preferably all, of the following features:

-   -   i) WR^(W2) is hydrogen;    -   ii) WR^(W4) is C1-C6 straight or branched alkyl or monocyclic or        bicyclic aliphatic; and    -   iii) WR^(W5) is selected from hydrogen, CN, CHF₂, NH₂, NH(C1-C6        alkyl), N(C1-C6 alkyl)₂, —NHC(O)(C1-C6 alkyl), —NHC(O)O(C1-C6        alkyl), —CH₂C(O)O(C1-C6 alkyl), —OH, —O(C1-C6 alkyl),        C(O)O(C1-C6 alkyl), or SO₂NH₂.

In one embodiment, compound of formula VA-1 has one, preferably more, ormore preferably all, of the following features:

-   -   i) WR^(W2) is halo, C1-C6 alkyl, CF₃, CN, or phenyl optionally        substituted with up to 3 substituents selected from C1-C4 alkyl,        —O(C1-C4 alkyl), or halo;    -   ii) WR^(W4) is CF₃, halo, C1-C6 alkyl, or C6-C10 cycloaliphatic;        and    -   iii) WR^(W5) is OH, NH₂, NH(C1-C6 alkyl), or N(C1-C6 alkyl).

In one embodiment, X—R^(X) is at the 6-position of the quinolinyl ring.In certain embodiments, X—R^(X) taken together is C1-C6 alkyl, —O—(C1-C6alkyl), or halo.

In one embodiment, X—R^(X) is at the 5-position of the quinolinyl ring.In certain embodiments, X—R^(X) taken together is —OH.

In another embodiment, the present invention provides compounds offormula VA-1, wherein WR^(W4) and WR^(W5) taken together form a 5-7membered ring containing 0-3 three heteroatoms selected from N, O, or S,wherein said ring is optionally substituted with up to threeWR^(W)substituents.

In certain embodiments, WR^(W4) and WR^(W5) taken together form anoptionally substituted 5-7 membered saturated, unsaturated, or aromaticring containing 0 heteroatoms. In other embodiments, WR^(W4) and WR^(W5)taken together form an optionally substituted 5-7 membered ringcontaining 1-3 heteroatoms selected from N, O, or S. In certain otherembodiments, WR^(W4) and WR^(W5) taken together form an optionallysubstituted saturated, unsaturated, or aromatic 5-7 membered ringcontaining 1 nitrogen heteroatom. In certain other embodiments, WR^(W4)and WR^(W5) taken together form an optionally substituted 5-7 memberedring containing 1 oxygen heteroatom.

In another embodiment, the present invention provides compounds offormula V-A-2:

wherein:

Y is CH₂, C(O)O, C(O), or S(O)₂;

m is 0-4; and

X, R^(X), W, and R^(W) are as defined above.

In one embodiment, compounds of formula VA-2 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, Y is C(O). In another embodiment, Y is C(O)O. Or, Yis S(O)₂. Or, Y is CH₂.

In one embodiment, m is 1 or 2. Or, m is 1. Or, m is 0.

In one embodiment, W is a bond.

In another embodiment, R^(W) is C1-C₆ aliphatic, halo, CF₃, or phenyloptionally substituted with C1-C6 alkyl, halo, cyano, or CF₃, wherein upto two methylene units of said C1-C6 aliphatic or C1-C6 alkyl isoptionally replaced with —CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—,—NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO₂NR′—, NR′SO₂—, or—NR′SO₂NR′—. In another embodiment, R′ above is C1-C4 alkyl. Exemplaryembodiments of WR^(W)include methyl, ethyl, propyl, tert-butyl, or2-ethoxyphenyl.

In another embodiment, R^(W) in Y—R^(W) is C1-C6 aliphatic optionallysubstituted with N(R″)₂, wherein R″ is hydrogen, C1-C6 alkyl, or two R″taken together form a 5-7 membered heterocyclic ring with up to 2additional heteroatoms selected from O, S, or NR′. Exemplary suchheterocyclic rings include pyrrolidinyl, piperidyl, morpholinyl, orthiomorpholinyl.

In another embodiment, the present invention provides compounds offormula V-A-3:

wherein:

Q is W;

R^(Q) is R^(W);

m is 0-4;

n is 0-4; and

X, R^(X), W, and R^(W) are as defined above.

In one embodiment, compounds of formula VA-3 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, n is 0-2.

In another embodiment, m is 0-2. In one embodiment, m is 0. In oneembodiment, m is 1. Or, m is 2.

In one embodiment, QR^(Q) taken together is halo, CF₃, OCF₃, CN, C1-C6aliphatic, O—C1-C6 aliphatic, O-phenyl, NH(C1-C6 aliphatic), or N(C1-C6aliphatic)₂, wherein said aliphatic and phenyl are optionallysubstituted with up to three substituents selected from C1-C6 alkyl,O—C1-C6 alkyl, halo, cyano, OH, or CF₃, wherein up to two methyleneunits of said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with—CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—,—NR′CO—, —S—, —NR′—, SOR′, SO₂R′, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. Inanother embodiment, R′ above is C1-C4 alkyl.

Exemplary QR^(Q) include methyl, isopropyl, sec-butyl, hydroxymethyl,CF₃, NMe₂, CN, CH₂CN, fluoro, chloro, OEt, OMe, SMe, OCF₃, OPh, C(O)OMe,C(O)O-iPr, S(O)Me, NHC(O)Me, or S(O)₂Me.

In another embodiment, the present invention provides compounds offormula V-A-4:

wherein X, R^(X), and R^(W) are as defined above.

In one embodiment, compounds of formula VA-4 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, R^(W) is C1-C12 aliphatic, C5-C10 cycloaliphatic, orC5-C7 heterocyclic ring, wherein said aliphatic, cycloaliphatic, orheterocyclic ring is optionally substituted with up to threesubstituents selected from C1-C6 alkyl, halo, cyano, oxo, OH, or CF₃,wherein up to two methylene units of said C1-C6 aliphatic or C1-C6 alkylis optionally replaced with —CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—,—NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO₂NR′—, NR′SO₂—, or—NR′SO₂NR′—. In another embodiment, R′ above is C1-C4 alkyl.

Exemplary R^(W) includes methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, t-butyl, n-pentyl, vinyl, cyanomethyl, hydroxymethyl,hydroxyethyl, hydroxybutyl, cyclohexyl, adamantyl, or—C(CH₃)₂—NHC(O)O-T, wherein T is C1-C4 alkyl, methoxyethyl, ortetrahydrofuranylmethyl.

In another embodiment, the present invention provides compounds offormula V-A-5:

wherein:

m is 0-4; and

X, R^(X), W, R^(W), and R′ are as defined above.

In one embodiment, compounds of formula VA-5 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, m is 0-2. Or, m is 1. Or, m is 2.

In another embodiment, both R′ are hydrogen. Or, one R′ is hydrogen andthe other R′ is C1-C4 alkyl, e.g., methyl. Or, both R′ are C1-C4 alkyl,e.g., methyl.

In another embodiment, m is 1 or 2, and R^(W) is halo, CF₃, CN, C1-C6aliphatic, O—C1-C6 aliphatic, or phenyl, wherein said aliphatic andphenyl are optionally substituted with up to three substituents selectedfrom C1-C6 alkyl, O—C1-C6 alkyl, halo, cyano, OH, or CF₃, wherein up totwo methylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionallyreplaced with —CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—,—OCONR′—, —NR′CO—, —S—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. Inanother embodiment, R′ above is C1-C4 alkyl.

Exemplary embodiments of R^(W) include chloro, CF₃, OCF₃, methyl, ethyl,n-propyl, isopropyl, n-butyl, t-butyl, methoxy, ethoxy, propyloxy, or2-ethoxyphenyl.

In another embodiment, the present invention provides compounds offormula V-A-6:

wherein:

ring B is a 5-7 membered monocyclic or bicyclic, heterocyclic orheteroaryl ring optionally substituted with up to n occurrences of-Q—R^(Q), wherein n is 0-4, and Q and R^(Q) are as defined above; and

Q, R^(Q), X, R^(X), W, and R^(W) are as defined above.

In one embodiment, compounds of formula VA-6 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, m is 0-2. Or, m is 0. Or m is 1.

In one embodiment, n is 0-2. Or, n is 0. Or, n is 1.

In another embodiment, ring B is a 5-7 membered monocyclic, heterocyclicring having up to 2 heteroatoms selected from O, S, or N, optionallysubstituted with up to n occurrences of -Q—R^(Q). Exemplary heterocyclicrings include N-morpholinyl, N-piperidinyl, 4-benzoyl-piperazin-1-yl,pyrrolidin-1-yl, or 4-methyl-piperidin-1-yl.

In another embodiment, ring B is a 5-6 membered monocyclic, heteroarylring having up to 2 heteroatoms selected from O, S, or N, optionallysubstituted with up to n occurrences of -Q—R^(Q). Exemplary such ringsinclude benzimidazol-2-yl, 5-methyl-furan-2-yl,2,5-dimethyl-pyrrol-1-yl, pyridine-4-yl, indol-5-yl, indol-2-yl,2,4-dimethoxy-pyrimidin-5-yl, furan-2-yl, furan-3-yl, 2-acyl-thien-2-yl,benzothiophen-2-yl, 4-methyl-thien-2-yl, 5-cyano-thien-2-yl,3-chloro-5-trifluoromethyl-pyridin-2-yl.

In another embodiment, the present invention provides compounds offormula V-B-1:

wherein:

one of Q₁ and Q₃ is N(WR^(W)) and the other of Q₁ and Q₃ is selectedfrom O, S, or N(WR^(W));

Q₂ is C(O), CH₂—C(O), C(O)—CH₂, CH₂, CH₂—CH₂, CF₂, or CF₂—CF₂;

m is 0-3; and

X, W, R^(X), and R^(W) are as defined above.

In one embodiment, compounds of formula V-B-1 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, Q₃ is N(WR^(W)); exemplary WR^(W) include hydrogen,C1-C6 aliphatic, C(O)C1-C6 aliphatic, or C(O)OC1-C6 aliphatic.

In another embodiment, Q₃ is N(WR^(W)), Q₂ is C(O), CH₂, CH₂—CH₂, and Q₁is O.

In another embodiment, the present invention provides compounds offormula V-B-2:

wherein:

R^(W1) is hydrogen or C1-C6 aliphatic;

each of R^(W3) is hydrogen or C1-C6 aliphatic; or

both R^(W3) taken together form a C3-C6 cycloalkyl or heterocyclic ringhaving up to two heteroatoms selected from O, S, or NR′, wherein saidring is optionally substituted with up to two WR^(W) substituents;

m is 0-4; and

X, R^(X), W, and R^(W) are as defined above.

In one embodiment, compounds of formula V-B-2 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, WR^(W1) is hydrogen, C1-C6 aliphatic, C(O)C1-C6aliphatic, or C(O)OC1-C6 aliphatic.

In another embodiment, each R^(W3) is hydrogen, C1-C4 alkyl. Or, bothR^(W3) taken together form a C3-C6 cycloaliphatic ring or 5-7 memberedheterocyclic ring having up to two heteroatoms selected from O, S, or N,wherein said cycloaliphatic or heterocyclic ring is optionallysubstituted with up to three substitutents selected from WR^(W1).Exemplary such rings include cyclopropyl, cyclopentyl, optionallysubstituted piperidyl, etc.

In another embodiment, the present invention provides compounds offormula V-B-3:

wherein:

Q₄ is a bond, C(O), C(O)O, or S(O)₂;

R^(W1) is hydrogen or C1-C6 aliphatic;

m is 0-4; and

X, W, R^(W), and R^(X) are as defined above.

In one embodiment, compounds of formula V-B-3 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0.

In one embodiment, Q₄ is C(O). Or Q₄ is C(O)O. In another embodiment,R^(W1) is C1-C6 alkyl. Exemplary R^(W1) include methyl, ethyl, ort-butyl.

In another embodiment, the present invention provides compounds offormula V-B-4:

wherein:

m is 0-4; and

X, R^(X), W, and R^(W) are as defined above.

In one embodiment, compounds of formula V-B-4 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, m is 0-2. Or, m is 0. Or, m is 1.

In another embodiment, said cycloaliphatic ring is a 5-membered ring.Or, said ring is a six-membered ring.

In another embodiment, the present invention provides compounds offormula V-B-5:

wherein:

ring A₂ is a phenyl or a 5-6 membered heteroaryl ring, wherein ring A₂and the phenyl ring fused thereto together have up 4 substituentsindependently selected from WR^(W);

m is 0-4; and

X, W, R^(W) and R^(X) are as defined above.

In one embodiment, compounds of formula V-B-5 have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, ring A₂ is an optionally substituted 5-membered ringselected from pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl,thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, or triazolyl.

In one embodiment, ring A₂ is an optionally substituted 5-membered ringselected from pyrrolyl, pyrazolyl, thiadiazolyl, imidazolyl, oxazolyl,or triazolyl. Exemplary such rings include:

wherein said ring is optionally substituted as set forth above.

In another embodiment, ring A₂ is an optionally substituted 6-memberedring. Exemplary such rings include pyridyl, pyrazinyl, or triazinyl. Inanother embodiment, said ring is an optionally pyridyl.

In one embodiment, ring A₂ is phenyl.

In another embodiment, ring A₂ is pyrrolyl, pyrazolyl, pyridyl, orthiadiazolyl.

Exemplary W in formula V-B-5 includes a bond, C(O), C(O)O or C1-C6alkylene.

Exemplary R^(W) in formula V-B-5 include cyano, halo, C1-C6 aliphatic,C3-C6 cycloaliphatic, aryl, 5-7 membered heterocyclic ring having up totwo heteroatoms selected from O, S, or N, wherein said aliphatic,phenyl, and heterocyclic are independently and optionally substitutedwith up to three substituents selected from C1-C6 alkyl, O—C1-C6 alkyl,halo, cyano, OH, or CF₃, wherein up to two methylene units of said C1-C6aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—,—CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—,—SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′ above isC1-C4 alkyl.

In one embodiment, the present invention provides compounds of formulaV-B-5-a:

wherein:

G₄ is hydrogen, halo, CN, CF₃, CHF₂, CH₂F, optionally substituted C1-C6aliphatic, aryl-C1-C6 alkyl, or a phenyl, wherein G₄ is optionallysubstituted with up to 4 WR^(W) substituents; wherein up to twomethylene units of said C1-C6 aliphatic or C1-C6 alkyl is optionallyreplaced with —CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—,—OCONR′—, —NR′CO—, —S—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—.

G₅ is hydrogen or an optionally substituted C1-C6 aliphatic; whereinsaid indole ring system is further optionally substituted with up to 3substituents independently selected from WR^(W).

In one embodiment, compounds of formula V-B-5-a have y occurrences ofX—R^(X), wherein y is 0-4. In one embodiment, y is 0. Or, y is 1. Or, yis 2.

In one embodiment, G₄ is hydrogen. Or, G₅ is hydrogen.

In another embodiment, G₄ is hydrogen, and G₅ is C1-C6 aliphatic,wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo,cyano, or CF₃, and wherein up to two methylene units of said C1-C6aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—,—CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—,—SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′ above isC1-C4 alkyl.

In another embodiment, G₄ is hydrogen, and G₅ is cyano, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl,CH₂C(O)OMe, (CH₂)₂—NHC(O)O-tert-butyl, or cyclopentyl.

In another embodiment, G₅ is hydrogen, and G₄ is halo, C1-C6 aliphaticor phenyl, wherein said aliphatic or phenyl is optionally substitutedwith C1-C6 alkyl, halo, cyano, or CF₃, wherein up to two methylene unitsof said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—,—CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—,—S—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′above is C1-C4 alkyl.

In another embodiment, G₅ is hydrogen, and G₄ is halo, CF₃,ethoxycarbonyl, t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl,(4-C(O)NH(CH₂)₂—NMe₂)-phenyl, 2-methoxy-4-chloro-phenyl, pyridine-3-yl,4-isopropylphenyl, 2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl,t-butyl, or piperidin-1-ylcarbonyl.

In another embodiment, G₄ and G₅ are both hydrogen, and the nitrogenring atom of said indole ring is substituted with C1-C6 aliphatic,C(O)(C1-C6 aliphatic), or benzyl, wherein said aliphatic or benzyl isoptionally substituted with C1-C6 alkyl, halo, cyano, or CF₃, wherein upto two methylene units of said C1-C6 aliphatic or C1-C6 alkyl isoptionally replaced with —CO—, —CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—,—NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—, —SO₂NR′—, NR′SO₂—, or—NR′SO₂NR′—. In another embodiment, R′ above is C1-C4 alkyl.

In another embodiment, G₄ and G₅ are both hydrogen, and the nitrogenring atom of said indole ring is substituted with acyl, benzyl,C(O)CH₂N(Me)C(O)CH₂NHMe, or ethoxycarbonyl.

In another embodiment, the present invention provides compounds offormula I′:

or pharmaceutically acceptable salts thereof,

wherein R′, R′, R³, R⁴, R′, R⁶, R⁷, and Ar¹ is as defined above forcompounds of formula I′.

In one embodiment, each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and Ar¹ incompounds of formula I′ is independently as defined above for any of theembodiments of compounds of formula I.

Representative compounds of the present invention are set forth below inTable 1 below.

TABLE 1 Cmpd No. Name 1N-[5-(5-chloro-2-methoxy-phenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide2 N-(3-methoxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 3N-[2-(2-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide4 N-(2-morpholinophenyl)-4-oxo-1H-quinoline-3-carboxamide 5N-[4-(2-hydroxy-1,1-dimethyl-ethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide6N-[3-(hydroxymethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide7N-(4-benzoylamino-2,5-diethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide8 N-(3-amino-4-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 94-oxo-N-(3-sulfamoylphenyl)-1H-quinoline-3-carboxamide 101,4-dihydro-N-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-yl)-4-oxoquinoline-3-carboxamide114-oxo-N-[2-[2-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide12 N-[2-(4-dimethylaminophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide13 N-(3-cyano-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 14[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]aminoformicacid methyl ester 15N-(2-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 164-oxo-N-(2-propylphenyl)-1H-quinoline-3-carboxamide 17N-(5-amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 18N-(9H-fluoren-1-yl)-4-oxo-1H-quinoline-3-carboxamide 194-oxo-N-(2-quinolyl)-1H-quinoline-3-carboxamide 20N-[2-(2-methylphenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide 214-oxo-N-[4-(2-pyridylsulfamoyl)phenyl]-1H-quinoline-3-carboxamide 224-Oxo-1,4-dihydro-quinoline-3-carboxylic acidN-(1′,2′-dihydrospiro[cyclopropane-1,3′-[3H]indol]- 6′-yl)-amide 23N-[2-(2-ethoxyphenyl)-5-hydroxy-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide24 4-oxo-N-(3-pyrrolidin-1-ylsulfonylphenyl)-1H-quinoline-3-carboxamide25 N-[2-(3-acetylaminophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 264-oxo-N-[2-(1-piperidyl)phenyl]-1H-quinoline-3-carboxamide 27N-[1-[2-[methyl-(2-methylaminoacetyl)-amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide 28[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid 2- methoxyethyl ester 291-isopropyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 30[2-isopropyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid methyl ester 31 4-oxo-N-(p-tolyl)-1H-quinoline-3-carboxamide 32N-(5-chloro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 33N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 34N-[4-(1,1-diethylpropyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide351,4-dihydro-N-(2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-4-oxoquinoline-3-carboxamide 36 N-(2-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide 37N-(1H-indol-7-yl)-4-oxo-1H-quinoline-3-carboxamide 38N-[2-(1H-indol-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 39[3-[(2,4-dimethoxy-3-quinolyl)carbonylamino]-4-tert-butyl-phenyl]aminoformicacid tert-butyl ester 40N-[2-(2-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 41N-(5-amino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 42N-[2-[[3-chloro-5-(trifluoromethyl)-2-pyridyl]oxy]phenyl]-4-oxo-1H-quinoline-3-carboxamide43N-[2-(3-ethoxyphenyl)-5-hydroxy-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide44 N-(2-methylbenzothiazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 45N-(2-cyano-3-fluoro-phenyl)-4-oxo-1H-quinoline-3-carboxamide 46N-[3-chloro-5-(2-morpholinoethylsulfonylamino)phenyl]-4-oxo-1H-quinoline-3-carboxamide47N-[4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide48 N-(5-chloro-2-fluoro-phenyl)-4-oxo-1H-quinoline-3-carboxamide 49N-[2-(2,6-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 504-oxo-N-(2,4,6-trimethylphenyl)-1H-quinoline-3-carboxamide 516-[(4-methyl-1-piperidyl)sulfonyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 52 N-[2-(m-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 534-oxo-N-(4-pyridyl)-1H-quinoline-3-carboxamide 544-oxo-N-(8-thia-7,9-diazabicyclo[4.3.0]nona-2,4,6,9-tetraen-5-yl)-1H-quinoline-3-carboxamide55N-(3-amino-2-methoxy-5-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide561,4-dihydro-N-(1,2,3,4-tetrahydro-6-hydroxynaphthalen-7-yl)-4-oxoquinoline-3-carboxamide57N-[4-(3-ethyl-2,6-dioxo-3-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide58N-[3-amino-4-(trifluoromethoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide59N-[2-(5-isopropyl-2-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide60[4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid tert-butyl ester 61N-(2,3-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 624-oxo-N-[3-(trifluoromethoxy)phenyl]-1H-quinoline-3-carboxamide 63N-[2-(2,4-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 644-oxo-N-(2-oxo-1,3-dihydrobenzoimidazol-5-yl)-1H-quinoline-3-carboxamide65 4-oxo-N-[5-(3-pyridyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide 66N-(2,2-difluorobenzo[1,3]dioxol-5-yl)-4-oxo-1H-quinoline-3-carboxamide67 6-ethyl-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide 683-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid methylester 69 N-(3-amino-4-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide70 4-oxo-N-[2-(4-pyridyl)phenyl]-1H-quinoline-3-carboxamide 713-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acidisopropyl ester 72 N-(2-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 734-oxo-N-(2-phenyl-3H-benzoimidazol-5-yl)-1H-quinoline-3-carboxamide 744-oxo-N-[5-(trifluoromethyl)-2-pyridyl]-1H-quinoline-3-carboxamide 754-oxo-N-(3-quinolyl)-1H-quinoline-3-carboxamide 76N-[2-(3,4-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 77N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 784-oxo-N-(2-sulfamoylphenyl)-1H-quinoline-3-carboxamide 79N-[2-(4-fluoro-3-methyl-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide80 N-(2-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 814-oxo-N-(3-propionylaminophenyl)-1H-quinoline-3-carboxamide 82N-(4-diethylamino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 83N-[2-(3-cyanophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 84N-(4-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 85N-[2-(3,4-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 86N-[4-[2-(aminomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide 874-oxo-N-(3-phenoxyphenyl)-1H-quinoline-3-carboxamide 88[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid tert-butyl ester 89N-(2-cyano-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 904-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide 91N-(3-chloro-2,6-diethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 92N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide93 N-[2-(5-cyano-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 94N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 95N-(2-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide 96N-[3-(cyanomethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide 97N-[2-(2,4-dimethoxypyrimidin-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide98 N-(5-dimethylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide99 4-oxo-N-(4-pentylphenyl)-1H-quinoline-3-carboxamide 100N-(1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide 101N-(5-amino-2-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 102N-[2-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]phenyl]-4-oxo-1H-quinoline-3-carboxamide1036-fluoro-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide104 N-(2-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 1051,4-dihydro-N-(3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-4-oxoquinoline-3-carboxamide106 N-(2-cyano-4,5-dimethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide1077-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylicacid tert- butyl ester 1084,4-dimethyl-7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylicacid tert-butyl ester 109N-(1-acetyl-2,3,4,5-tetrahydro-5,5-dimethyl-1H-benzo[b]azepin-8-yl)-1,4-dihydro-4-oxoquinoline-3-carboxamide 110N-[4-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1114-oxo-N-[2-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide 1126-ethoxy-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide 113N-(3-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 114[4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid tert-butyl ester 115N-[2-(2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1165-hydroxy-N-(1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 117N-(3-dimethylamino-4-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide118 N-[2-(1H-indol-5-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 119[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid ethyl ester 120N-(2-methoxy-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 121N-(3,4-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide 122N-(3,4-dimethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 123N-[2-(3-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1246-fluoro-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide125 N-(6-ethyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 126N-[3-hydroxy-4-[2-(2-methoxyethoxy)-1,1-dimethyl-ethyl]-phenyl]-4-oxo-1H-quinoline-3-carboxamide 127[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]aminoformicacid ethyl ester 1281,6-dimethyl-4-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide 129[2-ethyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid methyl ester 1304-hydroxy-N-(1H-indol-6-yl)-5,7-bis(trifluoromethyl)quinoline-3-carboxamide131 N-(3-amino-5-chloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide 132N-(5-acetylamino-2-ethoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 133N-[3-chloro-5-[2-(1-piperidyl)ethylsulfonylamino]phenyl]-4-oxo-1H-quinoline-3-carboxamide134N-[2-(4-methylsulfinylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide135 N-(2-benzo[1,3]dioxol-5-ylphenyl)-4-oxo-1H-quinoline-3-carboxamide136N-(2-hydroxy-3,5-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide1376-[(4-fluorophenyl)-methyl-sulfamoyl]-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 138N-[2-(3,5-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 139N-[2-(2,4-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 140N-(4-cyclohexylphenyl)-4-oxo-1H-quinoline-3-carboxamide 141[2-methyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid ethyl ester 1424-oxo-N-(2-sec-butylphenyl)-1H-quinoline-3-carboxamide 143N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide144 N-(3-hydroxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 1456-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-4-carboxylic acidethyl ester 1464-oxo-N-(1,7,9-triazabicyclo[4.3.0]nona-2,4,6,8-tetraen-5-yl)-1H-quinoline-3-carboxamide147 N-[2-(4-fluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide1484-oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide149 N-(3-acetylamino-4-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide1504-oxo-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-1H-quinoline-3-carboxamide 151N-[2-(4-methyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1524-oxo-N-(2-oxo-3H-benzooxazol-6-yl)-1H-quinoline-3-carboxamide 153N-[4-(1,1-diethyl-2,2-dimethyl-propyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide 154N-[3,5-bis(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1554-oxo-N-(2-pyridyl)-1H-quinoline-3-carboxamide 1564-oxo-N-[2-[2-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide157 N-(2-ethyl-5-methylamino-phenyl)-4-oxo-1H-quinoline-3-carboxamide158 4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 159[7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidmethyl ester 160N-(3-amino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 161N-[3-(2-ethoxyethoxy)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide162 N-(6-methoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 163N-[5-(aminomethyl)-2-(2-ethoxyphenyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide164 4-oxo-N-[3-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide 1654-oxo-N-(4-sulfamoylphenyl)-1H-quinoline-3-carboxamide 1664-[2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]benzoic acid methylester 167 N-(3-amino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide168 4-oxo-N-(3-pyridyl)-1H-quinoline-3-carboxamide 169N-(1-methyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 170N-(5-chloro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 171N-[2-(2,3-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 172N-(2-(benzo[b]thiophen-2-yl)phenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide173 N-(6-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 174N-[2-(5-acetyl-2-thienyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1754-Oxo-1,4-dihydro-quinoline-3-carboxylic acidN-(1′-Acetyl-1′,2′-dihydrospiro[cyclopropane-1,3′-3H-indol]-6′-yl)-amide 1764-oxo-N-[4-(trifluoromethoxy)phenyl]-1H-quinoline-3-carboxamide 177N-(2-butoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 1784-oxo-N-[2-(2-tert-butylphenoxy)phenyl]-1H-quinoline-3-carboxamide 179N-(3-carbamoylphenyl)-4-oxo-1H-quinoline-3-carboxamide 180N-(2-ethyl-6-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 1814-oxo-N-[2-(p-tolyl)phenyl]-1H-quinoline-3-carboxamide 182N-[2-(4-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 1837-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylicacid tert- butyl ester 184N-(1H-indol-6-yl)-4-oxo-2-(trifluoromethyl)-1H-quinoline-3-carboxamide185 N-(3-morpholinosulfonylphenyl)-4-oxo-1H-quinoline-3-carboxamide 186N-(3-cyclopentyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 187N-(1-acetyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 1886-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acidethyl ester 189 N-(4-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide190N-[2-(3-chloro-4-fluoro-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide191 4-oxo-N-(5-quinolyl)-1H-quinoline-3-carboxamide 192N-(3-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 193N-(2,6-dimethoxy-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 194N-(4-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide 195N-(5-methyl-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 196N-[5-(3,3-dimethylbutanoylamino)-2-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide197 4-oxo-N-[6-(trifluoromethyl)-3-pyridyl]-1H-quinoline-3-carboxamide198 N-(4-fluorophenyl)-4-oxo-1H-quinoline-3-carboxamide 199N-[2-(o-tolyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 2001,4-dihydro-N-(1,2,3,4-tetrahydro-1-hydroxynaphthalen-7-yl)-4-oxoquinoline-3-carboxamide201 N-(2-cyano-3-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 202N-[2-(5-chloro-2-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide203 N-(1-benzyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 204N-(4,4-dimethylchroman-7-yl)-4-oxo-1H-quinoline-3-carboxamide 205N-[2-(4-methoxyphenoxy)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide206N-[2-(2,3-dimethylphenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide207 2-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]aceticacid ethyl ester 208N-[4-(2-adamantyl)-5-hydroxy-2-methyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide209 N-[4-(hydroxymethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 2102,4-dimethoxy-N-(2-phenylphenyl)-quinoline-3-carboxamide 211N-(2-methoxy-5-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 212N-[3-(3-methyl-5-oxo-1,4-dihydropyrazol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide213 N-[2-(2,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide214 N-(3-methylsulfonylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide 2154-oxo-N-phenyl-1H-quinoline-3-carboxamide 216N-(3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide 217N-(1H-indazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 2186-fluoro-N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide 219 4-oxo-N-pyrazin-2-yl-1H-quinoline-3-carboxamide 220N-(2,3-dihydroxy-4,6-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide221[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-propyl-phenyl]aminoformicacid methyl ester 222N-(3-chloro-2-cyano-phenyl)-4-oxo-1H-quinoline-3-carboxamide 223N-[2-(4-methylsulfanylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide2244-oxo-N-[4-[2-[(2,2,2-trifluoroacetyl)aminomethyl]phenyl]phenyl]-1H-quinoline-3-carboxamide225[2-isopropyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid ethyl ester 226 4-oxo-N-(4-propylphenyl)-1H-quinoline-3-carboxamide227 N-[2-(3H-benzoimidazol-2-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide228 N-[2-(hydroxy-phenyl-methyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide229 N-(2-methylsulfanylphenyl)-4-oxo-1H-quinoline-3-carboxamide 230N-(2-methyl-1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 2313-[4-hydroxy-2-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-5-tert-butyl-phenyl]benzoicacid methyl ester 232N-(5-acetylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 233N-(1-acetylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide 2344-oxo-N-[5-(trifluoromethyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide235 N-(6-isopropyl-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 2364-oxo-N-[4-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide 237N-[5-(2-methoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide2387′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-quinoline],2′,3′-dihydro- carboxylic acid tert-butyl ester 239[4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid methyl ester 240N-(2-benzyloxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 2414-oxo-N-(8-quinolyl)-1H-quinoline-3-carboxamide 242N-(5-amino-2,4-dichloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide 243N-(5-acetylamino-2-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide2444-oxo-N-(6,7,8,9-tetrahydro-5H-carbazol-2-yl)-1H-quinoline-3-carboxamide245 N-[2-(2,4-dichlorophenoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide246 N-(3,4-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 2474-oxo-N-[2-(2-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide 248N-(3-acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 249[4-ethyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid methyl ester 250N-(5-acetylamino-2-methoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 251[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid isobutyl ester 252N-(2-benzoylphenyl)-4-oxo-1H-quinoline-3-carboxamide 2534-oxo-N-[2-[3-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide254 6-fluoro-N-(5-fluoro-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide255N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-6-pyrrolidin-1-ylsulfonyl-1H-quinoline-3-carboxamide256 N-(1H-benzotriazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 257N-(4-fluoro-3-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 258N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide 2594-oxo-N-(3-sec-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 260N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 261N-[2-(3,4-dimethylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 2621,4-dihydro-N-(3,4-dihydro-3-oxo-2H-benzo[b][1,4]thiazin-6-yl)-4-oxoquinoline-3-carboxamide263 N-(4-bromo-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 264N-(2,5-diethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 265N-(2-benzylphenyl)-4-oxo-1H-quinoline-3-carboxamide 266N-[5-hydroxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide267 4-oxo-N-(4-phenoxyphenyl)-1H-quinoline-3-carboxamide 2684-oxo-N-(3-sulfamoyl-4-tert-butyl-phenyl)-1H-quinoline-3-carboxamide 269[4-isopropyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid ethyl ester 270N-(2-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 271N-(3-amino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 272N-[3-(2-morpholinoethylsulfonylamino)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 273[7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidtert-butyl ester 2744-oxo-6-pyrrolidin-1-ylsulfonyl-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide2754-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide276 N-(4-morpholinosulfonylphenyl)-4-oxo-1H-quinoline-3-carboxamide 277N-[2-(3-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 2784-oxo-N-[2-[3-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide279N-[2-(2-methylsulfanylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide280 4-oxo-N-(6-quinolyl)-1H-quinoline-3-carboxamide 281N-(2,4-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 282N-(5-amino-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 283N-[2-(3-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 284N-(1H-indazol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 285N-[2-(2,3-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 2861,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-5-yl)-4-oxoquinoline-3-carboxamide287N-[2-fluoro-5-hydroxy-4-(1-methylcyclohexyl)-phenyl]-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide 288N-(5-fluoro-2-methoxycarbonyloxy-3-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide289 N-(2-fluoro-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 290N-[2-(3-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 291N-(2-chloro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide292 N-(5-chloro-2-phenoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 2934-oxo-N-[2-(1H-pyrrol-1-yl)phenyl]-1H-quinoline-3-carboxamide 294N-(1H-indol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 2954-oxo-N-(2-pyrrolidin-1-ylphenyl)-1H-quinoline-3-carboxamide 2962,4-dimethoxy-N-(2-tert-butylphenyl)-quinoline-3-carboxamide 297N-[2-(2,5-dimethyl-1H-pyrrol-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide298 [2-ethyl-5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid ethyl ester 2994-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide 300N-(4,4-dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide301N-[4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide302N-[2-[4-(hydroxymethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide303N-(2-acetyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide304[4-(2-ethoxyphenyl)-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenylmethyl]aminoformicacid tert-butyl ester 305N-[2-(4-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 306N-[2-(3-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 307N-[2-(3-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 308N-[2-(cyanomethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 309N-(3-isoquinolyl)-4-oxo-1H-quinoline-3-carboxamide 3104-oxo-N-(4-sec-butylphenyl)-1H-quinoline-3-carboxamide 311N-[2-(5-methyl-2-furyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 312N-[2-(2,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 313N-[2-(2-fluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 314N-(2-ethyl-6-isopropyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 315N-(2,6-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 316N-(5-acetylamino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide317 N-(2,6-dichlorophenyl)-4-oxo-1H-quinoline-3-carboxamide 3184-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide 3196-fluoro-N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide320 4-oxo-N-(2-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 321N-[2-(4-benzoylpiperazin-1-yl)phenyl]-4-oxo-1H-quinoline-3-carboxamide322 N-(2-ethyl-6-sec-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 323[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid methyl ester 324 N-(4-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide325 N-(2,6-diethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 326N-[2-(4-methylsulfonylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide327N-[5-(2-ethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide328 N-(3-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide 329N-[2-(o-tolyl)benzooxazol-5-yl]-4-oxo-1H-quinoline-3-carboxamide 330N-(2-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide 331N-(2-carbamoylphenyl)-4-oxo-1H-quinoline-3-carboxamide 332N-(4-ethynylphenyl)-4-oxo-1H-quinoline-3-carboxamide 333N-[2-[4-(cyanomethyl)phenyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide 3347′-[(4-oxo-1H-quinolin-3-ylcarbonyl)amino]-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′- dihydro-carboxylic acid tert-butyl ester 335N-(2-carbamoyl-5-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 336N-(2-butylphenyl)-4-oxo-1H-quinoline-3-carboxamide 337N-(5-hydroxy-2,4-ditert-butyl-phenyl)-N-methyl-4-oxo-1H-quinoline-3-carboxamide338 N-(3-methyl-1H-indol-4-yl)-4-oxo-1H-quinoline-3-carboxamide 339N-(3-cyano-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 340N-(3-methylsulfonylamino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide341[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid neopentyl ester 342N-[5-(4-isopropylphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide343N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide344 N-[2-(2-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 3456-fluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide 3464-oxo-N-phenyl-7-(trifluoromethyl)-1H-quinoline-3-carboxamide 347N-[5-[4-(2-dimethylaminoethylcarbamoyl)phenyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide 348N-[2-(4-ethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 3494-oxo-N-(2-phenylsulfonylphenyl)-1H-quinoline-3-carboxamide 350N-(1-naphthyl)-4-oxo-1H-quinoline-3-carboxamide 351N-(5-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 3522-[6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indol-3-yl]ethylaminoformicacid tert-butyl ester 353[3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformicacid tert-butyl ester 354N-[2-[(cyclohexyl-methyl-amino)methyl]phenyl]-4-oxo-1H-quinoline-3-carboxamide355 N-[2-(2-methoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 356N-(5-methylamino-2-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 357N-(3-isopropyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 3586-chloro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide 359N-[3-(2-dimethylaminoethylsulfonylamino)-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 360N-[4-(difluoromethoxy)phenyl]-4-oxo-1H-quinoline-3-carboxamide 361N-[2-(2,5-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 362N-(2-chloro-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 363N-[2-(2-fluoro-3-methoxy-phenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide364 N-(2-methyl-8-quinolyl)-4-oxo-1H-quinoline-3-carboxamide 365N-(2-acetylphenyl)-4-oxo-1H-quinoline-3-carboxamide 3664-oxo-N-[2-[4-(trifluoromethyl)phenyl]phenyl]-1H-quinoline-3-carboxamide367 N-[2-(3,5-dichlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide368 N-(3-amino-4-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 369N-(2,4-dichloro-6-cyano-phenyl)-4-oxo-1H-quinoline-3-carboxamide 370N-(3-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide 3714-oxo-N-[2-(trifluoromethylsulfanyl)phenyl]-1H-quinoline-3-carboxamide372 N-[2-(4-methyl-1-piperidyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide373 N-indan-4-yl-4-oxo-1H-quinoline-3-carboxamide 3744-hydroxy-N-(1H-indol-6-yl)-2-methylsulfanyl-quinoline-3-carboxamide 3751,4-dihydro-N-(1,2,3,4-tetrahydronaphthalen-6-yl)-4-oxoquinoline-3-carboxamide376 4-oxo-N-(2-phenylbenzooxazol-5-yl)-1H-quinoline-3-carboxamide 3776,8-difluoro-4-hydroxy-N-(1H-indol-6-yl)quinoline-3-carboxamide 378N-(3-amino-4-methoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide 379N-[3-acetylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide380 N-(2-ethoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 3814-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 382[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-propyl-phenyl]aminoformicacid ethyl ester 383N-(3-ethyl-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide 384N-[2-(2,5-difluorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 385N-[2-(2,4-difluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide386 N-(3,3-dimethylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide 387N-[2-methyl-3-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide3884-oxo-N-[2-[4-(trifluoromethoxy)phenyl]phenyl]-1H-quinoline-3-carboxamide389 N-(3-benzylphenyl)-4-oxo-1H-quinoline-3-carboxamide 390N-[3-(aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide391 N-[2-(4-isobutylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 392N-(6-chloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 393N-[5-amino-2-(2-ethoxyphenyl)-phenyl]-4-oxo-1H-quinoline-3-carboxamide394 1,6-dimethyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 395N-[4-(1-adamantyl)-2-fluoro-5-hydroxy-phenyl]-4-hydroxy-quinoline-3-carboxamide396[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid tetrahydrofuran-3-ylmethyl ester 3974-oxo-N-(4-phenylphenyl)-1H-quinoline-3-carboxamide 3984-oxo-N-[2-(p-tolylsulfonylamino)phenyl]-1H-quinoline-3-carboxamide 399N-(2-isopropyl-5-methylamino-phenyl)-4-oxo-1H-quinoline-3-carboxamide400 N-(6-morpholino-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 401N-[2-(2,3-dimethylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 4024-oxo-N-(5-phenyl-2-pyridyl)-1H-quinoline-3-carboxamide 403N-[2-fluoro-5-hydroxy-4-(1-methylcyclooctyl)-phenyl]-4-hydroxy-quinoline-3-carboxamide404N-[5-(2,6-dimethoxyphenyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide405 N-(4-chlorophenyl)-4-oxo-1H-quinoline-3-carboxamide 4066-[(4-fluorophenyl)-methyl-sulfamoyl]-4-oxo-N-(5-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 407N-(2-fluoro-5-hydroxy-4-tert-butyl-phenyl)-5-hydroxy-4-oxo-1H-quinoline-3-carboxamide408 N-(3-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 409N-(5-dimethylamino-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 4104-oxo-N-[2-(4-phenoxyphenyl)phenyl]-1H-quinoline-3-carboxamide 4117-chloro-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 4126-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-7-carboxylic acidethyl ester 413 4-oxo-N-(2-phenoxyphenyl)-1H-quinoline-3-carboxamide 414N-(3H-benzoimidazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide 415N-(3-hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide 416[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid propyl ester 417N-(2-(benzo[b]thiophen-3-yl)phenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide418 N-(3-dimethylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide 419N-(3-acetylaminophenyl)-4-oxo-1H-quinoline-3-carboxamide 4202-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propanoicacid ethyl ester 421N-[5-methoxy-4-tert-butyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide422N-(5,6-dimethyl-3H-benzoimidazol-2-yl)-4-oxo-1H-quinoline-3-carboxamide423 N-[3-(2-ethoxyethyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide424 N-[2-(4-chlorophenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 425N-(4-isopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide 426N-(4-chloro-5-hydroxy-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide4275-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroisoquinoline-2-carboxylicacid tert- butyl ester 428N-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 429N-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide430 N-(2-isopropyl-6-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 431N-(3-aminophenyl)-4-oxo-1H-quinoline-3-carboxamide 432N-[2-(4-isopropylphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 433N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide434 N-(2,5-dimethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 435N-[2-(2-fluorophenoxy)-3-pyridyl]-4-oxo-1H-quinoline-3-carboxamide 436N-[2-(3,4-dimethoxyphenyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 437N-benzo[1,3]dioxol-5-yl-4-oxo-1H-quinoline-3-carboxamide 438N-[5-(difluoromethyl)-2,4-ditert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide439 N-(4-methoxyphenyl)-4-oxo-1H-quinoline-3-carboxamide 440N-(2,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-1,4-dihydro-4-oxoquinoline-3-carboxamide 441N-[3-methylsulfonylamino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide442 4-oxo-N-[3-(1-piperidylsulfonyl)phenyl]-1H-quinoline-3-carboxamide443 4-oxo-N-quinoxalin-6-yl-1H-quinoline-3-carboxamide 4445-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-benzoic acidmethyl ester 445N-(2-isopropenylphenyl)-4-oxo-1H-quinoline-3-carboxamide 446N-(1,1-dioxobenzothiophen-6-yl)-4-oxo-1H-quinoline-3-carboxamide 447N-(3-cyanophenyl)-4-oxo-1H-quinoline-3-carboxamide 4484-oxo-N-(4-tert-butylphenyl)-1H-quinoline-3-carboxamide 449N-(m-tolyl)-4-oxo-1H-quinoline-3-carboxamide 450N-[4-(1-hydroxyethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 451N-(4-cyano-2-ethyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 4524-oxo-N-(4-vinylphenyl)-1H-quinoline-3-carboxamide 453N-(3-amino-4-chloro-phenyl)-4-oxo-1H-quinoline-3-carboxamide 454N-(2-methyl-5-phenyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide 455N-[4-(1-adamantyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide 4564-oxo-N-[3-(trifluoromethylsulfanyl)phenyl]-1H-quinoline-3-carboxamide457 N-(4-morpholinophenyl)-4-oxo-1H-quinoline-3-carboxamide 458N-[3-(2-hydroxyethoxy)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide459 N-(o-tolyl)-4-oxo-1H-quinoline-3-carboxamide 460[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid butyl ester 461 4-oxo-N-(2-phenylphenyl)-1H-quinoline-3-carboxamide462 N-(3-dimethylamino-4-propyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide463 N-(4-ethylphenyl)-4-oxo-1H-quinoline-3-carboxamide 4645-hydroxy-N-(5-hydroxy-2,4-ditert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide465[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenylmethyl]aminoformicacid tert-butyl ester 466N-(2,6-diisopropylphenyl)-4-oxo-1H-quinoline-3-carboxamide 467N-(2,3-dihydrobenzofuran-5-yl)-4-oxo-1H-quinoline-3-carboxamide 4681-methyl-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 4694-oxo-N-(2-phenylphenyl)-7-(trifluoromethyl)-1H-quinoline-3-carboxamide470 4-oxo-N-(4-phenylsulfanylphenyl)-1H-quinoline-3-carboxamide 471[3-[(4-oxo-1H-quinoline-3-yl)carbonylamino]-4-propyl-phenyl]aminoformicacid methyl ester 472[4-ethyl-3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]aminoformicacid ethyl ester 4731-isopropyl-4-oxo-N-(2-tert-butylphenyl)-1H-quinoline-3-carboxamide 474N-(3-methyl-2-oxo-3H-benzooxazol-5-yl)-4-oxo-1H-quinoline-3-carboxamide475 N-(2,5-dichloro-3-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 476N-(2-cyano-5-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide477 N-(5-fluoro-2-pyridyl)-4-oxo-1H-quinoline-3-carboxamide 4784-oxo-N-(3-tert-butyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide 479N-(1H-indol-6-yl)-5-methoxy-4-oxo-1H-quinoline-3-carboxamide 4801-ethyl-6-methoxy-4-oxo-N-phenyl-1H-quinoline-3-carboxamide 481N-(2-naphthyl)-4-oxo-1H-quinoline-3-carboxamide 482[7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidethyl ester 483N-[2-fluoro-5-hydroxy-4-(1-methylcycloheptyl)-phenyl]-4-hydroxy-quinoline-3-carboxamide484N-(3-methylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide485N-(3-dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

In another embodiment, the present invention provides compounds usefulas intermediates in the synthesis of compounds of formula I. In oneembodiment, such compounds have formula A-I:

or a salt thereof;wherein:

G₁ is hydrogen, R′, C(O)R′, C(S)R′, S(O)R′, S(O)₂R′, Si(CH₃)₂R′,P(O)(OR′)₃, P(S)(OR′)₃, or B(OR′)₂;

G₂ is halo, CN, CF₃, isopropyl, or phenyl wherein said isopropyl orphenyl is optionally substituted with up to 3 substituents independentlyselected from WR^(W), wherein W and R^(W) are as defined above forformula I and embodiments thereof;

G₃ is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G₃ isoptionally substituted with up to 3 substituents independently selectedfrom WR^(W), wherein W and R^(W) are as defined above for formula I andembodiments thereof;

provided that when G₁ is methoxy, G₃ is tert-butyl, then G₂ is not2-amino-4-methoxy-5-tert-butyl-phenyl.

In one embodiment, the present invention provides compounds of formulaA-I, provided that when G₂ and G₃ each is t-butyl, then G₁ is nothydrogen.

In another embodiment:

G₁ is hydrogen;

G₂ is halo or isopropyl, wherein said isopropyl is optionallysubstituted with up to 3 substituents independently selected from R′;and

G₃ is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G₃ isoptionally substituted with up to 3 substituents independently selectedfrom R′.

In another embodiment:

G₁ is hydrogen;

G₂ is halo, preferably fluoro; and

G₃ is a C3-C10 cycloaliphatic ring, wherein said G₃ is optionallysubstituted with up to 3 substituents independently selected frommethyl, ethyl, propyl, or butyl.

In another embodiment:

G₁ is hydrogen;

G₂ is CN, halo, or CF₃; and

G₃ is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G₃ isoptionally substituted with up to 3 substituents independently selectedfrom R′.

In another embodiment:

G₁ is hydrogen;

G₂ is phenyl is optionally substituted with up to 3 substituentsindependently selected from —OC 1-C4 alkyl, CF₃, halo, or CN; and

G₃ is an isopropyl or a C3-C10 cycloaliphatic ring, wherein said G₃ isoptionally substituted with up to 3 substituents independently selectedfrom R′.

Exemplary G₃ include optionally substituted cyclopentyl, cyclohexyl,cycloheptyl, or adamantyl. Or, G3 is C₃-C₈ branched aliphatic chain.Exemplary G3 include isopropyl, t-butyl, 3,3-diethyl-prop-3-yl, or3,3-diethyl-2,2-dimethyl-prop-3-yl.

In another embodiment:

G₁ is hydrogen;

G₂ is t-butyl; and

G₃ is a t-butyl.

In another embodiment, the present invention provides a compound offormula A-II:

or a salt thereof, wherein:

G₄ is hydrogen, halo, CN, CF₃, CHF₂, CH₂F, optionally substituted C1-C6aliphatic, aralkyl, or a phenyl ring optionally substituted with up to 4WR^(W)substituents;

G₅ is hydrogen or an optionally substituted C1-C6 aliphatic;

provided that both, G₄ and G₅, are not simultaneously hydrogen;

wherein said indole ring system is further optionally substituted withup to 3 substituents independently selected from WR^(W).

In one embodiment, G₄ is hydrogen. Or, G₅ is hydrogen.

In another embodiment, G₄ is hydrogen, and G₅ is C1-C6 aliphatic,wherein said aliphatic is optionally substituted with C1-C6 alkyl, halo,cyano, or CF₃, and wherein up to two methylene units of said C1-C6aliphatic or C1-C6 alkyl is optionally replaced with —CO—, —CONR′—,—CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—, —S—, —NR′—,—SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′ above isC1-C4 alkyl.

In another embodiment, G₄ is hydrogen, and G₅ is cyano, methyl, ethyl,propyl, isopropyl, butyl, sec-butyl, t-butyl, cyanomethyl, methoxyethyl,CH₂C(O)OMe, (CH₂)₂—NHC(O)O-tert-But, or cyclopentyl.

In another embodiment, G₅ is hydrogen, and G₄ is halo, C1-C6 aliphaticor phenyl, wherein said aliphatic or phenyl is optionally substitutedwith C1-C6 alkyl, halo, cyano, or CF₃, wherein up to two methylene unitsof said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—,—CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—,—S—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′above is C1-C4 alkyl.

In another embodiment, G₅ is hydrogen, and G₄ is halo, ethoxycarbonyl,t-butyl, 2-methoxyphenyl, 2-ethoxyphenyl, 4-C(O)NH(CH₂)₂—NMe₂,2-methoxy-4-chloro-phenyl, pyridine-3-yl, 4-isopropylphenyl,2,6-dimethoxyphenyl, sec-butylaminocarbonyl, ethyl, t-butyl, orpiperidin-1-ylcarbonyl.

In a related embodiment of formula A-II, the nitrogen ring atom of saidindole ring is substituted with C1-C6 aliphatic, C(O)(C1-C6 aliphatic),or benzyl, wherein said aliphatic or benzyl is optionally substitutedwith C1-C6 alkyl, halo, cyano, or CF₃, wherein up to two methylene unitsof said C1-C6 aliphatic or C1-C6 alkyl is optionally replaced with —CO—,—CONR′—, —CO₂—, —OCO—, —NR′CO₂—, —O—, —NR′CONR′—, —OCONR′—, —NR′CO—,—S—, —NR′—, —SO₂NR′—, NR′SO₂—, or —NR′SO₂NR′—. In another embodiment, R′above is C1-C4 alkyl.

In another embodiment the nitrogen ring atom of said indole ring issubstituted with acyl, benzyl, C(O)CH₂N(Me)C(O)CH₂NHMe, orethoxycarbonyl.

4. General Synthetic Schemes

Compounds of the present invention are readily prepared by methods knownin the art. Illustrated below are exemplary methods for the preparationof compounds of the present invention.

The scheme below illustrates the synthesis of acid precursors of thecompounds of the present invention.

Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C:

Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C:

Synthesis of Acid Precursors P-IV-A, P-IV-B or P-IV-C

Synthesis of Amine Precursor P-III-A:

Synthesis of Amine Precursor P-IV-A:

Synthesis of Amine Precursor P-V-A-1:

Synthesis of Amine Precursor P-V-A-1:

Synthesis of Amine Precursor P-V-A-1:

Synthesis of Amine Precursor P-V-A-1:

Synthesis of Amine Precursors P-V-A-1 or P-V-A-2:

Synthesis of Amine Precursors P-V-A-1 or P-V-A-2:

Synthesis of Amine Precursors P-V-A-1:

Synthesis of Amine Precursors P-V-A-3:

Synthesis of Amine Precursors P-V-B-1:

Synthesis of Amine Precursors P-V-B-1:

Synthesis of Amine Precursors P-V-B-1:

Synthesis of Amine Precursors P-V-B-2:

Synthesis of Amine Precursors P-V-B-3:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-B-5:

Synthesis of Amine Precursors P-V-A-3 and P-V-A-6:

Synthesis of Amine Precursors P-V-A-4:

Synthesis of Amine Precursors P-V-A-4:

Synthesis of Amine Precursors P-V-B-4:

Synthesis of Amine Precursors P-V-B-4:

Synthesis of Compounds of Formula I:

Synthesis of Compounds of Formula I′:

Synthesis of Compounds of formula V-B-5:

Synthesis of Compounds of formula V-B-5:

Synthesis of Compounds of Formula V-A-2 & V-A-5:

Synthesis of compounds of formula V-B-2:

Synthesis of compounds of formula V-A-2:

Synthesis of compounds of formula V-A-4:

In the schemes above, the radical R′ employed therein is a substituent,e.g., R^(W) as defined hereinabove. One of skill in the art will readilyappreciate that synthetic routes suitable for various substituents ofthe present invention are such that the reaction conditions and stepsemployed do not modify the intended substituents.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that areuseful as modulators of ABC transporters and thus are useful in thetreatment of disease, disorders or conditions such as cystic fibrosis,hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetesmellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear plasy,Pick's disease, several polyglutamine neurological disorders such asHuntington, spinocerebullar ataxia type I, spinal and bulbar muscularatrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren'sdisease.

Accordingly, in another aspect of the present invention,pharmaceutically acceptable compositions are provided, wherein thesecompositions comprise any of the compounds as described herein, andoptionally comprise a pharmaceutically acceptable carrier, adjuvant orvehicle. In certain embodiments, these compositions optionally furthercomprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative or a prodrug thereof. Accordingto the present invention, a pharmaceutically acceptable derivative or aprodrug includes, but is not limited to, pharmaceutically acceptablesalts, esters, salts of such esters, or any other adduct or derivativewhich upon administration to a patient in need thereof is capable ofproviding, directly or indirectly, a compound as otherwise describedherein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like, andare commensurate with a reasonable benefit/risk ratio. A“pharmaceutically acceptable salt” means any non-toxic salt or salt ofan ester of a compound of this invention that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention or an inhibitorily active metabolite orresidue thereof.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge, et al. describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporatedherein by reference. Pharmaceutically acceptable salts of the compoundsof this invention include those derived from suitable inorganic andorganic acids and bases. Examples of pharmaceutically acceptable,nontoxic acid addition salts are salts of an amino group formed withinorganic acids such as hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid and perchloric acid or with organic acids such asacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid,succinic acid or malonic acid or by using other methods used in the artsuch as ion exchange. Other pharmaceutically acceptable salts includeadipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate,bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate,formate, fumarate, glucoheptonate, glycerophosphate, gluconate,hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, lower alkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. Remington'sPharmaceutical Sciences, Sixteenth Edition, E. W. Martin (MackPublishing Co., Easton, Pa., 1980) discloses various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention. Some examples ofmaterials which can serve as pharmaceutically acceptable carriersinclude, but are not limited to, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, such as human serum albumin, buffersubstances such as phosphates, glycine, sorbic acid, or potassiumsorbate, partial glyceride mixtures of saturated vegetable fatty acids,water, salts or electrolytes, such as protamine sulfate, disodiumhydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zincsalts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, woolfat, sugars such as lactose, glucose and sucrose; starches such as cornstarch and potato starch; cellulose and its derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients such as cocoa butter andsuppository waxes; oils such as peanut oil, cottonseed oil; saffloweroil; sesame oil; olive oil; corn oil and soybean oil; glycols; such apropylene glycol or polyethylene glycol; esters such as ethyl oleate andethyl laurate; agar; buffering agents such as magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releasingagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, the present invention provides a method oftreating a condition, disease, or disorder implicated by ABC transporteractivity, e.g., CFTR. In certain embodiments, the present inventionprovides a method of treating a condition, disease, or disorderimplicated by a deficiency of the ABC transporter activity, the methodcomprising administering a composition comprising a compound of formula(I) to a subject, preferably a mammal, in need thereof.

In certain embodiments, the present invention provides a method oftreating cystic fibrosis, hereditary emphysema, hereditaryhemochromatosis, coagulation-fibrinolysis deficiencies, such as proteinC deficiency, Type 1 hereditary angioedema, lipid processingdeficiencies, such as familial hypercholesterolemia, Type 1chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, suchas I-cell disease/pseudo-Hurler, mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,myleoperoxidase deficiency, primary hypoparathyroidism, melanoma,glycanosis CDG type 1, congenital hyperthyroidism, osteogenesisimperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetesinsipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Toothsyndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, progressive supranuclear plasy, Pick's disease, severalpolyglutamine neurological disorders such as Huntington, spinocerebullarataxia type I, spinal and bulbar muscular atrophy, dentatorubalpallidoluysian, and myotonic dystrophy, as well as spongiformencephalopathies, such as hereditary Creutzfeldt-Jakob disease (due toprion protein processing defect), Fabry disease, Straussler-Scheinkersyndrome, COPD, dry-eye disease, or Sjogren's disease, comprising thestep of administering to said mammal an effective amount of acomposition comprising a compound of the present invention.

According to an alternative preferred embodiment, the present inventionprovides a method of treating cystic fibrosis comprising the step ofadministering to said mammal a composition comprising the step ofadministering to said mammal an effective amount of a compositioncomprising a compound of the present invention.

According to the invention an “effective amount” of the compound orpharmaceutically acceptable composition is that amount effective fortreating or lessening the severity of one or more of cystic fibrosis,hereditary emphysema, hereditary hemochromatosis,coagulation-fibrinolysis deficiencies, such as protein C deficiency,Type 1 hereditary angioedema, lipid processing deficiencies, such asfamilial hypercholesterolemia, Type 1 chylomicronemia,abetalipoproteinemia, lysosomal storage diseases, such as I-celldisease/pseudo-Hurler, mucopolysaccharidoses, Sandhof/Tay-Sachs,Crigler-Najjar type II, polyendocrinopathy/hyperinsulemia, Diabetesmellitus, Laron dwarfism, myleoperoxidase deficiency, primaryhypoparathyroidism, melanoma, glycanosis CDG type 1, congenitalhyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia,ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI,Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease,neurodegenerative diseases such as Alzheimer's disease, Parkinson'sdisease, amyotrophic lateral sclerosis, progressive supranuclear plasy,Pick's disease, several polyglutamine neurological disorders such asHuntington, spinocerebullar ataxia type I, spinal and bulbar muscularatrophy, dentatorubal pallidoluysian, and myotonic dystrophy, as well asspongiform encephalopathies, such as hereditary Creutzfeldt-Jakobdisease (due to prion protein processing defect), Fabry disease,Straussler-Scheinker syndrome, COPD, dry-eye disease, or Sjogren'sdisease.

The compounds and compositions, according to the method of the presentinvention, may be administered using any amount and any route ofadministration effective for treating or lessening the severity of oneor more of cystic fibrosis, hereditary emphysema, hereditaryhemochromatosis, coagulation-fibrinolysis deficiencies, such as proteinC deficiency, Type 1 hereditary angioedema, lipid processingdeficiencies, such as familial hypercholesterolemia, Type 1chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, suchas I-cell disease/pseudo-Hurler, mucopolysaccharidoses,Sandhof/Tay-Sachs, Crigler-Najjar type II,polyendocrinopathy/hyperinsulemia, Diabetes mellitus, Laron dwarfism,myleoperoxidase deficiency, primary hypoparathyroidism, melanoma,glycanosis CDG type 1, congenital hyperthyroidism, osteogenesisimperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetesinsipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Toothsyndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases suchas Alzheimer's disease, Parkinson's disease, amyotrophic lateralsclerosis, progressive supranuclear plasy, Pick's disease, severalpolyglutamine neurological disorders such as Huntington, spinocerebullarataxia type I, spinal and bulbar muscular atrophy, dentatorubalpallidoluysian, and myotonic dystrophy, as well as spongiformencephalopathies, such as hereditary Creutzfeldt-Jakob disease (due toprion protein processing defect), Fabry disease, Straussler-Scheinkersyndrome, COPD, dry-eye disease, or Sjogren's disease.

In one embodiment, the compounds and compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in a patient.

In certain embodiments, the compounds and compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in patients who exhibit residual CFTR activity in the apicalmembrane of respiratory and non-respiratory epithelia. The presence ofresidual CFTR activity at the epithelial surface can be readily detectedusing methods known in the art, e.g., standard electrophysiological,biochemical, or histochemical techniques. Such methods identify CFTRactivity using in vivo or ex vivo electrophysiological techniques,measurement of sweat or salivary Cl⁻ concentrations, or ex vivobiochemical or histochemical techniques to monitor cell surface density.Using such methods, residual CFTR activity can be readily detected inpatients heterozygous or homozygous for a variety of differentmutations, including patients homozygous or heterozygous for the mostcommon mutation, ΔF508.

In another embodiment, the compounds and compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in patients who have residual CFTR activity induced oraugmented using pharmacological methods or gene therapy. Such methodsincrease the amount of CFTR present at the cell surface, therebyinducing a hitherto absent CFTR activity in a patient or augmenting theexisting level of residual CFTR activity in a patient.

In one embodiment, the compounds and compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in patients within certain genotypes exhibiting residual CFTRactivity, e.g., class III mutations (impaired regulation or gating),class IV mutations (altered conductance), or class V mutations (reducedsynthesis) (Lee R. Choo-Kang, Pamela L., Zeitlin, Type I, II, III, IV,and V cystic fibrosis Transmembrane Conductance Regulator Defects andOpportunities of Therapy; Current Opinion in Pulmonary Medicine6:521-529, 2000). Other patient genotypes that exhibit residual CFTRactivity include patients homozygous for one of these classes orheterozygous with any other class of mutations, including class Imutations, class TI mutations, or a mutation that lacks classification.

In one embodiment, the compounds and compositions of the presentinvention are useful for treating or lessening the severity of cysticfibrosis in patients within certain clinical phenotypes, e.g., amoderate to mild clinical phenotype that typically correlates with theamount of residual CFTR activity in the apical membrane of epithelia.Such phenotypes include patients exhibiting pancreatic sufficiency orpatients diagnosed with idiopathic pancreatitis and congenital bilateralabsence of the vas deferens, or mild lung disease.

The exact amount required will vary from subject to subject, dependingon the species, age, and general condition of the subject, the severityof the infection, the particular agent, its mode of administration, andthe like. The compounds of the invention are preferably formulated indosage unit form for ease of administration and uniformity of dosage.The expression “dosage unit form” as used herein refers to a physicallydiscrete unit of agent appropriate for the patient to be treated. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the present invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific effective dose level for any particular patient or organismwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; the activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed, andlike factors well known in the medical arts. The term “patient”, as usedherein, means an animal, preferably a mammal, and most preferably ahuman.

The pharmaceutically acceptable compositions of this invention can beadministered to humans and other animals orally, rectally, parenterally,intracistemally, intravaginally, intraperitoneally, topically (as bypowders, ointments, or drops), bucally, as an oral or nasal spray, orthe like, depending on the severity of the infection being treated. Incertain embodiments, the compounds of the invention may be administeredorally or parenterally at dosage levels of about 0.01 mg/kg to about 50mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subjectbody weight per day, one or more times a day, to obtain the desiredtherapeutic effect.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, delayed absorption ofa parenterally administered compound form is accomplished by dissolvingor suspending the compound in an oil vehicle. Injectable depot forms aremade by forming microencapsule matrices of the compound in biodegradablepolymers such as polylactide-polyglycolide. Depending upon the ratio ofcompound to polymer and the nature of the particular polymer employed,the rate of compound release can be controlled. Examples of otherbiodegradable polymers include poly(orthoesters) and poly(anhydrides).Depot injectable formulations are also prepared by entrapping thecompound in liposomes or microemulsions that are compatible with bodytissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms are prepared by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are usefulas modulators of ABC transporters. Thus, without wishing to be bound byany particular theory, the compounds and compositions are particularlyuseful for treating or lessening the severity of a disease, condition,or disorder where hyperactivity or inactivity of ABC transporters isimplicated in the disease, condition, or disorder. When hyperactivity orinactivity of an ABC transporter is implicated in a particular disease,condition, or disorder, the disease, condition, or disorder may also bereferred to as a “ABC transporter-mediated disease, condition ordisorder”. Accordingly, in another aspect, the present inventionprovides a method for treating or lessening the severity of a disease,condition, or disorder where hyperactivity or inactivity of an ABCtransporter is implicated in the disease state.

The activity of a compound utilized in this invention as a modulator ofan ABC transporter may be assayed according to methods describedgenerally in the art and in the Examples herein.

It will also be appreciated that the compounds and pharmaceuticallyacceptable compositions of the present invention can be employed incombination therapies, that is, the compounds and pharmaceuticallyacceptable compositions can be administered concurrently with, prior to,or subsequent to, one or more other desired therapeutics or medicalprocedures. The particular combination of therapies (therapeutics orprocedures) to employ in a combination regimen will take into accountcompatibility of the desired therapeutics and/or procedures and thedesired therapeutic effect to be achieved. It will also be appreciatedthat the therapies employed may achieve a desired effect for the samedisorder (for example, an inventive compound may be administeredconcurrently with another agent used to treat the same disorder), orthey may achieve different effects (e.g., control of any adverseeffects). As used herein, additional therapeutic agents that arenormally administered to treat or prevent a particular disease, orcondition, are known as “appropriate for the disease, or condition,being treated”.

In one embodiment, the additional agent is selected from a mucolyticagent, bronchodialator, an anti-biotic, an anti-infective agent, ananti-inflammatory agent, a CFTR modulator other than a compound of thepresent invention, or a nutritional agent.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptablecompositions thereof may also be incorporated into compositions forcoating an implantable medical device, such as prostheses, artificialvalves, vascular grafts, stents and catheters. Accordingly, the presentinvention, in another aspect, includes a composition for coating animplantable device comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. In still anotheraspect, the present invention includes an implantable device coated witha composition comprising a compound of the present invention asdescribed generally above, and in classes and subclasses herein, and acarrier suitable for coating said implantable device. Suitable coatingsand the general preparation of coated implantable devices are describedin U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings aretypically biocompatible polymeric materials such as a hydrogel polymer,polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylacticacid, ethylene vinyl acetate, and mixtures thereof. The coatings mayoptionally be further covered by a suitable topcoat of fluorosilicone,polysaccarides, polyethylene glycol, phospholipids or combinationsthereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to modulating ABC transporteractivity in a biological sample or a patient (e.g., in vitro or invivo), which method comprises administering to the patient, orcontacting said biological sample with a compound of formula I or acomposition comprising said compound. The term “biological sample”, asused herein, includes, without limitation, cell cultures or extractsthereof, biopsied material obtained from a mammal or extracts thereof,and blood, saliva, urine, feces, semen, tears, or other body fluids orextracts thereof.

Modulation of ABC transporter activity, e.g., CFTR, in a biologicalsample is useful for a variety of purposes that are known to one ofskill in the art. Examples of such purposes include, but are not limitedto, the study of ABC transporters in biological and pathologicalphenomena; and the comparative evaluation of new modulators of ABCtransporters.

In yet another embodiment, a method of modulating activity of an anionchannel in vitro or in vivo, is provided comprising the step ofcontacting said channel with a compound of formula (I). In preferredembodiments, the anion channel is a chloride channel or a bicarbonatechannel. In other preferred embodiments, the anion channel is a chloridechannel.

According to an alternative embodiment, the present invention provides amethod of increasing the number of functional ABC transporters in amembrane of a cell, comprising the step of contacting said cell with acompound of formula (I). The term “functional ABC transporter” as usedherein means an ABC transporter that is capable of transport activity.In preferred embodiments, said functional ABC transporter is CFTR.

According to another preferred embodiment, the activity of the ABCtransporter is measured by measuring the transmembrane voltagepotential. Means for measuring the voltage potential across a membranein the biological sample may employ any of the known methods in the art,such as optical membrane potential assay or other electrophysiologicalmethods.

The optical membrane potential assay utilizes voltage-sensitive FRETsensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission can be monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

In another aspect the present invention provides a kit for use inmeasuring the activity of a ABC transporter or a fragment thereof in abiological sample in vitro or in vivo comprising (i) a compositioncomprising a compound of formula (I) or any of the above embodiments;and (ii) instructions for a) contacting the composition with thebiological sample and b) measuring activity of said ABC transporter or afragment thereof. In one embodiment, the kit further comprisesinstructions for a) contacting an additional composition with thebiological sample; b) measuring the activity of said ABC transporter ora fragment thereof in the presence of said additional compound, and c)comparing the activity of the ABC transporter in the presence of theadditional compound with the density of the ABC transporter in thepresence of a composition of formula (I). In preferred embodiments, thekit is used to measure the density of CFTR.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

EXAMPLES Example 1 General Scheme to Prepare Acid Moities

Specific Example 2-Phenylaminomethylene-malonic Acid Diethyl Ester

A mixture of aniline (25.6 g, 0.28 mol) and diethyl2-(ethoxymethylene)malonate (62.4 g, 0.29 mol) was heated at 140-150° C.for 2 h. The mixture was cooled to room temperature and dried underreduced pressure to afford 2-phenylaminomethylene-malonic acid diethylester as a solid, which was used in the next step without furtherpurification. ¹H NMR (d-DMSO) δ 11.00 (d, 1H), 8.54 (d, J=13.6 Hz, 1H),7.36-7.39 (m, 2H), 7.13-7.17 (m, 3H), 4.17-4.33 (m, 4H), 1.18-1.40 (m,6H).

4-Hydroxyquinoline-3-carboxylic Acid Ethyl Ester

A 1 L three-necked flask fitted with a mechanical stirrer was chargedwith 2-phenylaminomethylene-malonic acid diethyl ester (26.3 g, 0.1mol), polyphosphoric acid (270 g) and phosphoryl chloride (750 g). Themixture was heated to about 70° C. and stirred for 4 h. The mixture wascooled to room temperature, and filtered. The residue was treated withaqueous Na₂CO₃ solution, filtered, washed with water and dried.4-Hydroxyquinoline-3-carboxylic acid ethyl ester was obtained as a palebrown solid (15.2 g, 70%). The crude product was used in next stepwithout further purification.

A-1; 4-Oxo-1,4-dihydroquinoline-3-carboxylic Acid

4-Hydroxyquinoline-3-carboxylic acid ethyl ester (15 g, 69 mmol) wassuspended in sodium hydroxide solution (2N, 150 mL) and stirred for 2 hunder reflux. After cooling, the mixture was filtered, and the filtratewas acidified to pH 4 with 2N HCl. The resulting precipitate wascollected via filtration, washed with water and dried under vacuum togive 4-oxo-1,4-dihydroquinoline-3-carboxylic acid (A-1) as a pale whitesolid (10.5 g, 92%). ¹H NMR (d-DMSO) δ 15.34 (s, 1H), 13.42 (s, 1H),8.89 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.88 (m, 1H), 7.81 (d, J=8.4 Hz,1H), 7.60 (m, 1H).

Specific Example A-2; 6-Fluoro-4-hydroxy-quinoline-3-carboxylic Acid

6-Fluoro-4-hydroxy-quinoline-3-carboxylic acid (A-2) was synthesizedfollowing the general scheme above starting from 4-fluoro-phenylamine.Overall yield (53%). ¹H NMR (DMSO-d₆) δ 15.2 (br s, 1H), 8.89 (s, 1H),7.93-7.85 (m, 2H), 7.80-7.74 (m, 1H); ESI-MS 207.9 m/z (MH⁺).

Example 2

2-Bromo-5-methoxy-phenylamine

A mixture of 1-bromo-4-methoxy-2-nitro-benzene (10 g, 43 mmol) and RaneyNi (5 g) in ethanol (100 mL) was stirred under H₂ (1 atm) for 4 h atroom temperature. Raney Ni was filtered off and the filtrate wasconcentrated under reduced pressure. The resulting solid was purified bycolumn chromatography to give 2-bromo-5-methoxy-phenylamine (7.5 g,86%).

2-[(2-Bromo-5-methoxy-phenylamino)-methylene]-malonic Acid Diethyl Ester

A mixture of 2-bromo-5-methoxy-phenylamine (540 mg, 2.64 mmol) anddiethyl 2-(ethoxymethylene)malonate (600 mg, 2.7 mmol) was stirred at100° C. for 2 h. After cooling, the reaction mixture was recrystallizedfrom methanol (10 mL) to give2-[(2-bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl esteras a yellow solid (0.8 g, 81%).

8-Bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid EthylEster

2-[(2-Bromo-5-methoxy-phenylamino)-methylene]-malonic acid diethyl ester(9 g, 24.2 mmol) was slowly added to polyphosphoric acid (30 g) at 120°C. The mixture was stirred at this temperature for additional 30 min andthen cooled to room temperature. Absolute ethanol (30 mL) was added andthe resulting mixture was refluxed for 30 min. The mixture was basifiedwith aqueous sodium bicarbonate at 25° C. and extracted with EtOAc(4×100 mL). The organic layers were combined, dried and the solventevaporated to give8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethylester (2.3 g, 30%).

5-Methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid Ethyl Ester

A mixture of 8-bromo-5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid ethyl ester (2.3 g, 7.1 mmol), sodium acetate (580 mg, 7.1 mmol)and 10% Pd/C (100 mg) in glacial acetic acid (50 ml) was stirred underH₂ (2.5 atm) overnight. The catalyst was removed via filtration, and thereaction mixture was concentrated under reduced pressure. The resultingoil was dissolved in CH₂Cl₂ (100 mL) and washed with aqueous sodiumbicarbonate solution and water. The organic layer was dried, filteredand concentrated. The crude product was purified by columnchromatography to afford5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester as ayellow solid (1 g, 57%).

A-4; 5-Methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid

A mixture of 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acidethyl ester (1 g, 7.1 mmol) in 10% NaOH solution (50 mL) was heated toreflux overnight and then cooled to room temperature. The mixture wasextracted with ether. The aqueous phase was separated and acidified withconc. HCl solution to pH 1-2. The resulting precipitate was collected byfiltration to give 5-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylicacid (A-4) (530 mg, 52%). ¹H NMR (DMSO) δ: 15.9 (s, 1H), 13.2 (br, 1H),8.71 (s, 1H), 7.71 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.82 (d,J=8.4 Hz, 1H), 3.86 (s, 3H); ESI-MS 219.9 m/z (MH⁺).

Example 3

Sodium 2-(mercapto-phenylamino-methylene)-malonic Acid Diethyl Ester

To a suspension of NaH (60% in mineral oil, 6 g, 0.15 mol) in Et₂O atroom temperature was added dropwise, over a 30 minutes period, ethylmalonate (24 g, 0.15 mol). Phenyl isothiocyanate (20.3 g, 0.15 mol) wasthen added dropwise with stirring over 30 min. The mixture was refluxedfor 1 h and then stirred overnight at room temperature. The solid wasseparated, washed with anhydrous ether (200 mL), and dried under vacuumto yield sodium 2-(mercapto-phenylamino-methylene)-malonic acid diethylester as a pale yellow powder (46 g, 97

2-(Methylsulfanyl-phenylamino-methylene)-malonic Acid Diethyl Ester

Over a 30 min period, methyl iodide (17.7 g, 125 mmol) was addeddropwise to a solution of sodium2-(mercapto-phenylamino-methylene)-malonic acid diethyl ester (33 g, 104mmol) in DMF (100 mL) cooled in an ice bath. The mixture was stirred atroom temperature for 1 h, and then poured into ice water (300 mL). Theresulting solid was collected via filtration, washed with water anddried to give 2-(methylsulfanyl-phenylamino-methylene)-malonic aciddiethyl ester as a pale yellow solid (27 g, 84%).

4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic Acid Ethyl Ester

A mixture of 2-(methylsulfanyl-phenylamino-methylene)-malonic aciddiethyl ester (27 g, 87 mmol) in 1,2-dichlorobenzene (100 mL) was heatedto reflux for 1.5 h. The solvent was removed under reduced pressure andthe oily residue was triturated with hexane to afford a pale yellowsolid that was purified by preparative HPLC to yield4-hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g,35%).

A-16; 2-Methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid

4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g,30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1.5h. After cooling, the mixture was acidified with concentrated HCl to pH4. The resulting solid was collected via filtration, washed with water(100 mL) and MeOH (100 mL) to give2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16) asa white solid (6 g, 85%). ¹H NMR (CDCl₃) δ 16.4 (br s, 1H), 11.1 (br s,1H), 8.19 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.84 (t, J=8, 8 Hz,1H), 7.52 (t, J=8 Hz, 1H), 2.74 (s, 3H); ESI-MS 235.9 m/z (MH⁺).

Example 4

2,2,2-Trifluoro-N-phenyl-acetimidoyl Chloride

A mixture of Ph₃P (138.0 g, 526 mmol), Et₃N (21.3 g, 211 mmol), CCl₄(170 mL) and TFA (20 g, 175 mmol) was stirred for 10 min in an ice-bath.Aniline (19.6 g, 211 mmol) was dissolved in CCl₄ (20 mL) was added. Themixture was stirred at reflux for 3 h. The solvent was removed undervacuum and hexane was added. The precipitates (Ph₃PO and Ph₃P) werefiltered off and washed with hexane. The filtrate was distilled underreduced pressure to yield 2,2,2-trifluoro-N-phenyl-acetimidoyl chloride(19 g), which was used in the next step without further purification.

2-(2,2,2-Trifluoro-1-phenylimino-ethyl)-malonic Acid Diethyl Ester

To a suspension of NaH (3.47 g, 145 mmol, 60% in mineral oil) in THF(200 mL) was added diethyl malonate (18.5 g, 116 mmol) at 0° C. Themixture was stirred for 30 min at this temperature and2,2,2-trifluoro-N-phenyl-acetimidoyl chloride (19 g, 92 mmol) was addedat 0° C. The reaction mixture was allowed to warm to room temperatureand stirred overnight. The mixture was diluted with CH₂Cl₂, washed withsaturated sodium bicarbonate solution and brine. The combined organiclayers were dried over Na₂SO₄, filtered and concentrated to provide2-(2,2,2-trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester,which was used directly in the next step without further purification.

4-Hydroxy-2-trifluoromethyl-quinoline-3-carboxylic Acid Ethyl Ester

2-(2,2,2-Trifluoro-1-phenylimino-ethyl)-malonic acid diethyl ester washeated at 210° C. for 1 h with continuous stirring. The mixture waspurified by column chromatography (petroleum ether) to yield4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (12g, 24% over 3 steps).

A-15; 4-Hydroxy-2-trifluoromethyl-quinoline-3-carboxylic Acid

A suspension of 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylic acidethyl ester (5 g, 17.5 mmol) in 10% aqueous NaOH solution was heated atreflux for 2 h. After cooling, dichloromethane was added and the aqueousphase was separated and acidified with concentrated HCl to pH 4. Theresulting precipitate was collected via filtration, washed with waterand Et₂O to provide 4-hydroxy-2-trifluoromethyl-quinoline-3-carboxylicacid (A-15) (3.6 g, 80%). ¹H NMR (DMSO-d₆) δ 8.18-8.21 (d, J=7.8 Hz,1H), 7.92-7.94 (d, J=8.4 Hz, 1H), 7.79-7.83 (t, J=14.4 Hz, 1H),7.50-7.53 (t, J=15 Hz, 1H); ESI-MS 257.0 m/z (MH⁺).

Example 5

3-Amino-cyclohex-2-enone

A mixture of cyclohexane-1,3-dione (56.1 g, 0.5 mol) and AcONH₄ (38.5 g,0.5 mol) in toluene was heated at reflux for 5 h with a Dean-starkapparatus. The resulting oily layer was separated and concentrated underreduced pressure to give 3-amino-cyclohex-2-enone (49.9 g, 90%), whichwas used directly in the next step without further purification.

2-[(3-Oxo-cyclohex-1-enylamino)-methylene]-malonic Acid Diethyl Ester

A mixture of 3-amino-cyclohex-2-enone (3.3 g, 29.7 mmol) and diethyl2-(ethoxymethylene)malonate (6.7 g, 31.2 mmol) was stirred at 130° C.for 4 h. The reaction mixture was concentrated under reduced pressureand the resulting oil was purified by column chromatography (silica gel,ethyl acetate) to give2-[(3-oxo-cyclohex-1-enylamino)-methylene]-malonic acid diethyl ester(7.5 g, 90%).

4,5-Dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic Acid Ethyl Ester

A mixture of 2-[(3-oxo-cyclohex-1-enylamino)-methylene]-malonic aciddiethyl ester (2.8 g, 1 mmol) and diphenylether (20 mL) was refluxed for15 min. After cooling, n-hexane (80 mL) was added. The resulting solidwas isolated via filtration and recrystallized from methanol to give4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylic acid ethyl ester(1.7 g 72%).

5-Hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid Ethyl Ester

To a solution of 4,5-dioxo-1,4,5,6,7,8-hexahydro-quinoline-3-carboxylicacid ethyl ester (1.6 g, 6.8 mmol) in ethanol (100 mL) was added iodine(4.8 g, 19 mmol). The mixture was refluxed for 19 h and thenconcentrated under reduced pressure. The resulting solid was washed withethyl acetate, water and acetone, and then recrystallized from DMF togive 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid ethyl ester(700 mg, 43%).

A-3; 5-Hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic Acid

A mixture of 5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acidethyl ester (700 mg, 3 mmol) in 10% NaOH (20 ml) was heated at refluxovernight. After cooling, the mixture was extracted with ether. Theaqueous phase was separated and acidified with conc. HCl to pH 1-2. Theresulting precipitate was collected via filtration to give5-hydroxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-3) (540 mg,87%). ¹H NMR (DMSO-d₆) δ 13.7 (br, 1H), 13.5 (br, 1H), 12.6 (s, 1H),8.82 (s, 1H), 7.68 (t, J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.82 (d,J=8.4 Hz, 1H); ESI-MS 205.9 m/z (MH⁺).

Example 6

2,4-Dichloroquinoline

A suspension of quinoline-2,4-diol (15 g, 92.6 mmol) in POCl₃ was heatedat reflux for 2 h. After cooling, the solvent was removed under reducedpressure to yield 2,4-dichloroquinoline, which was used without furtherpurification.

2,4-Dimethoxyquinoline

To a suspension of 2,4-dichloroquinoline in MeOH (100 mL) was addedsodium methoxide (50 g). The mixture was heated at reflux for 2 days.After cooling, the mixture was filtered. The filtrate was concentratedunder reduced pressure to yield a residue that was dissolved in waterand extracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄ and concentrated to give 2,4-dimethoxyquinoline as a white solid(13 g, 74% over 2 steps).

Ethyl 2,4-dimethoxyquinoline-3-carboxylate

To a solution of 2,4-dimethoxyquinoline (11.5 g, 60.8 mmol) in anhydrousTHF was added dropwise n-BuLi (2.5 M in hexane, 48.6 mL, 122 mmol) at 0°C. After stirring for 1.5 h at 0° C., the mixture was added to asolution of ethyl chloroformate in anhydrous THF and stirred at 0° C.for additional 30 min and then at room temperature overnight. Thereaction mixture was poured into water and extracted with CH₂Cl₂. Theorganic layer was dried over Na₂SO₄ and concentrated under vacuum. Theresulting residue was purified by column chromatography (petroleumether/EtOAc=50/1) to give ethyl 2,4-dimethoxyquinoline-3-carboxylate(9.6 g, 60%).

A-17; 2,4-Dimethoxyquinoline-3-carboxylic Acid

Ethyl 2,4-dimethoxyquinoline-3-carboxylate (1.5 g, 5.7 mmol) was heatedat reflux in NaOH solution (10%, 100 mL) for 1 h. After cooling, themixture was acidified with concentrated HCl to pH 4. The resultingprecipitate was collected via filtration and washed with water and etherto give 2,4-dimethoxyquinoline-3-carboxylic acid (A-17) as a white solid(670 mg, 50%). ¹H NMR (CDCl₃) δ 8.01-8.04 (d, J=12 Hz, 1H), 7.66-7.76(m, 2H), 7.42-7.47 (t, J=22 Hz, 2H), 4.09 (s, 3H). 3.97 (s, 3H); ESI-MS234.1 m/z (MH⁺).

Commercially Available Acids

Acid Name A-5 6,8-Difluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acidA-6 6-[(4-Fluoro-phenyl)-methyl-sulfamoyl]-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-76-(4-Methyl-piperidine-1-sulfonyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-84-Oxo-6-(pyrrolidine-1-sulfonyl)-1,4-dihydro-quinoline-3- carboxylicacid A-10 6-Ethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-116-Ethoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-124-Oxo-7-trifluoromethyl-1,4-dihydro-quinoline-3-carboxylic acid A-137-Chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-144-Oxo-5,7-bis-trifluoromethyl-1,4-dihydro-quinoline-3- carboxylic acidA-20 1-Methyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-211-Isopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-221,6-Dimethyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-231-Ethyl-6-methoxy-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid A-246-Chloro-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid

Amine Moieties

N-1 Substituted 6-aminoindoles

Example 1 General Scheme

Specific Example

1-Methyl-6-nitro-1H-indole

To a solution of 6-nitroindole (4.05 g 25 mmol) in DMF (50 mL) was addedK₂CO₃ (8.63 g, 62.5 mmol) and MeI (5.33 g, 37.5 mmol). After stirring atroom temperature overnight, the mixture was poured into water andextracted with ethyl acetate. The combined organic layers were driedover Na₂SO₄ and concentrated under vacuum to give the product1-methyl-6-nitro-1H-indole (4.3 g, 98%).

B-1; 1-Methyl-1H-indol-6-ylamine

A suspension of 1-methyl-6-nitro-1H-indole (4.3 g, 24.4 mmol) and 10%Pd—C (0.43 g) in EtOH (50 mL) was stirred under H₂ (1 atm) at roomtemperature overnight. After filtration, the filtrate was concentratedand acidified with HCl-MeOH (4 mol/L) to give1-methyl-1H-indol-6-ylamine hydrochloride salt (B-1) (1.74 g, 49%) as agrey powder. ¹H NMR (DMSO-d₆): δ 9.10 (s, 2H), 7.49 (d, J=8.4 Hz, 1H),7.28 (d, J=2.0 Hz, 1H), 7.15 (s, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.38 (d,J=2.8 Hz, 1H), 3.72 (s, 3H); ESI-MS146.08 m/z (MH⁺).

Other Examples

B-2; 1-Benzyl-1H-indol-6-ylamine

1-Benzyl-1H-indol-6-ylamine (B-2) was synthesized following the generalscheme above starting from 6-nitroindole and benzyl bromide. Overallyield (˜40%). HPLC ret. time 2.19 min, 10-99% CH₃CN, 5 min run; ESI-MS223.3 m/z (MH⁺).

B-3; 1-(6-Amino-indol-1-yl)-ethanone

1-(6-Amino-indol-1-yl)-ethanone (B-3) was synthesized following thegeneral scheme above starting from 6-nitroindole and acetyl chloride.Overall yield (˜40%). HPLC ret. time 0.54 min, 10-99% CH₃CN, 5 min run;ESI-MS 175.1 m/z (MH⁺).

Example 2

{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic AcidEthyl Ester

To a stirred solution of (tert-butoxycarbonyl-methyl-amino)-acetic acid(37 g, 0.2 mol) and Et₃N (60.6 g, 0.6 mol) in CH₂Cl₂ (300 mL) was addedisobutyl chloroformate (27.3 g, 0.2 mmol) dropwise at −20° C. underargon. After stirring for 0.5 h, methylamino-acetic acid ethyl esterhydrochloride (30.5 g, 129 mmol) was added dropwise at −20° C. Themixture was allowed to warm to room temperature (c.a. 1 h) and quenchedwith water (500 mL). The organic layer was separated, washed with 10%citric acid solution, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by column chromatography (petroleum ether/EtOAc1:1) to give{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acidethyl ester (12.5 g, 22

{[2-(tert-Butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic Acid

A suspension of{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acidethyl ester (12.3 g, 42.7 mmol) and LiOH (8.9 g, 214 mmol) in H₂O (20mL) and THF (100 mL) was stirred overnight. Volatile solvent was removedunder vacuum and the residue was extracted with ether (2×100 mL). Theaqueous phase was acidified to pH 3 with dilute HCl solution, and thenextracted with CH₂Cl₂ (2×300 mL). The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated under vacuum togive {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-aceticacid as a colorless oil (10 g, 90%). ¹H NMR (CDCl₃) δ 7.17 (br s, 1H),4.14-4.04 (m, 4H), 3.04-2.88 (m, 6H), 1.45-1.41 (m, 9H); ESI-MS 282.9m/z (M+Na⁺).

Methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamicAcid tert-butyl Ester

To a mixture of{[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid(13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL)was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen.The solution was stirred at room temperature for 20 min. A solution of6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reactionmixture was heated at 60° C. for 18 h. The solvent was evaporated andthe crude mixture was re-partitioned between EtOAc and water. Theorganic layer was separated, washed with water (×3), dried over Na₂SO₄and concentrated. Diethyl ether followed by EtOAc was added. Theresulting solid was collected via filtration, washed with diethyl etherand air dried to yieldmethyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamicacid tert-butyl ester (6.42 g, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 1.37(m, 9H), 2.78 (m, 3H), 2.95 (d, J=1.5 Hz, 1H), 3.12 (d, J=2.1 Hz, 2H),4.01 (d, J=13.8 Hz, 0.6H), 4.18 (d, J=12.0 Hz, 1.4H), 4.92 (d, J=3.4 Hz,1.4H), 5.08 (d, J=11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m,1H), 8.35 (d, J=3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min,10-99% CH₃CN, 5 min run; ESI-MS 405.5 m/z (MH⁺).

B-26;({[2-(6-Amino-indol-1-yl)-2-oxo-ethyl]-methyl-carbamoyl}-methyl)-methyl-carbamicAcid tert-butyl Ester

A mixture ofmethyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamicacid tert-butyl ester (12.4 g, 30.6 mmol), SnCl₂.2H₂O (34.5 g, 153.2mmol) and DIEA (74.8 mL, 429 mmol) in ethanol (112 mL) was heated to 70°C. for 3 h. Water and EtOAc were added and the mixture was filteredthrough a short plug of Celite. The organic layer was separated, driedover Na₂SO₄ and concentrated to yield({[2-(6-Amino-indol-1-yl)-2-oxo-ethyl]-methyl-carbamoyl}-methyl)-methyl-carbamicacid tert-butyl ester (B-26) (11.4 g, quant.). HPLC ret. time 2.11 min,10-99% CH₃CN, 5 min run; ESI-MS 375.3 m/z (MH⁺).

2-Substituted 6-aminoindoles

Example 1

B-4-a; (3-Nitro-phenyl)-hydrazine Hydrochloride Salt

3-Nitro-phenylamine (27.6 g, 0.2 mol) was dissolved in a mixture of H₂O(40 mL) and 37% HCl (40 mL). A solution of NaNO₂ (13.8 g, 0.2 mol) inH₂O (60 mL) was added at 0° C., followed by the addition of SnCl₂.H₂O(135.5 g, 0.6 mol) in 37% HCl (100 mL) at that temperature. Afterstirring at 0° C. for 0.5 h, the solid was isolated via filtration andwashed with water to give (3-nitro-phenyl)-hydrazine hydrochloride salt(B-4-a) (27.6 g, 73%).

2-[(3-Nitro-phenyl)-hydrazono]-propionic Acid Ethyl Ester

(3-Nitro-phenyl)-hydrazine hydrochloride salt (B-4-a) (30.2 g, 0.16 mol)and 2-oxo-propionic acid ethyl ester (22.3 g, 0.19 mol) was dissolved inethanol (300 mL). The mixture was stirred at room temperature for 4 h.The solvent was evaporated under reduced pressure to give2-[(3-nitro-phenyl)-hydrazono]-propionic acid ethyl ester, which wasused directly in the next step.

B-4-b; 4-Nitro-1H-indole-2-carboxylic acid ethyl ester and6-Nitro-1H-indole-2-carboxylic Acid Ethyl Ester

2-[(3-Nitro-phenyl)-hydrazono]-propionic acid ethyl ester from thepreceding step was dissolved in toluene (300 mL). PPA (30 g) was added.The mixture was heated at reflux overnight and then cooled to roomtemperature. The solvent was removed to give a mixture of4-nitro-1H-indole-2-carboxylic acid ethyl ester and6-nitro-1H-indole-2-carboxylic acid ethyl ester (B-4-b) (15 g, 40%).

B-4; 2-Methyl-1H-indol-6-ylamine

To a suspension of LiAlH₄ (7.8 g, 0.21 mol) in THF (300 mL) was addeddropwise a mixture of 4-nitro-1H-indole-2-carboxylic acid ethyl esterand 6-nitro-1H-indole-2-carboxylic acid ethyl ester (B-4-b) (6 g, 25.7mmol) in THF (50 mL) at 0° C. under N₂. The mixture was heated at refluxovernight and then cooled to 0° C. H₂O (7.8 mL) and 10% NaOH (7.8 mL)were added to the mixture at 0° C. The insoluble solid was removed viafiltration. The filtrate was dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography to afford 2-methyl-1H-indol-6-ylamine (B-4) (0.3g, 8%). ¹H NMR (CDCl₃) δ 7.57 (br s, 1H), 7.27 (d, J=8.8 Hz, 1H), 6.62(s, 1H), 6.51-6.53 (m, 1H), 6.07 (s, 1H), 3.59-3.25 (br s, 2H), 2.37 (s,3H); ESI-MS 147.2 m/z (MH⁺).

Example 2

6-Nitro-1H-indole-2-carboxylic acid and 4-Nitro-1H-indole-2-carboxylicAcid

A mixture of 4-nitro-1H-indole-2-carboxylic acid ethyl ester and6-nitro-1H-indole-2-carboxylic acid ethyl ester (B-4-b) (0.5 g, 2.13mmol) in 10% NaOH (20 mL) was heated at reflux overnight and then cooledto room temperature. The mixture was extracted with ether. The aqueousphase was separated and acidified with HCl to pH 1-2. The resultingsolid was isolated via filtration to give a mixture of6-nitro-1H-indole-2-carboxylic acid and 4-nitro-1H-indole-2-carboxylicacid (0.3 g, 68%).

6-Nitro-1H-indole-2-carboxylic acid amide and4-Nitro-1H-indole-2-carboxylic Acid Amide

A mixture of 6-nitro-1H-indole-2-carboxylic acid and4-nitro-1H-indole-2-carboxylic acid (12 g, 58 mmol) and SOCl₂ (50 mL, 64mmol) in benzene (150 mL) was refluxed for 2 h. The benzene andexcessive SOCl₂ was removed under reduced pressure. The residue wasdissolved in CH₂Cl₂ (250 mL). NH₄OH (21.76 g, 0.32 mol) was addeddropwise at 0° C. The mixture was stirred at room temperature for 1 h.The resulting solid was isolated via filtration to give a crude mixtureof 6-nitro-1H-indole-2-carboxylic acid amide and4-nitro-1H-indole-2-carboxylic acid amide (9 g, 68%), which was useddirectly in the next step.

6-Nitro-1H-indole-2-carbonitrile and 4-Nitro-1H-indole-2-carbonitrile

A mixture of 6-nitro-1H-indole-2-carboxylic acid amide and4-nitro-1H-indole-2-carboxylic acid amide (5 g, 24 mmol) was dissolvedin CH₂Cl₂ (200 mL). Et₃N (24.24 g, 0.24 mol) was added, followed by theaddition of (CF₃CO)₂O (51.24 g, 0.24 mol) at room temperature. Themixture was stirred for 1 h and poured into water (100 mL). The organiclayer was separated. The aqueous layer was extracted with EtOAc (100mL×3). The combined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure. The crude residue was purified bycolumn chromatography to give a mixture of6-nitro-1H-indole-2-carbonitrile and 4-nitro-1H-indole-2-carbonitrile(2.5 g, 55%).

B-5; 6-Amino-1H-indole-2-carbonitrile

A mixture of 6-nitro-1H-indole-2-carbonitrile and4-nitro-1H-indole-2-carbonitrile (2.5 g, 13.4 mmol) and Raney Ni (500mg) in EtOH (50 mL) was stirred at room temperature under H₂ (1 atm) for1 h. Raney Ni was filtered off. The filtrate was evaporated underreduced pressure and purified by column chromatography to give6-amino-1H-indole-2-carbonitrile (B-5) (1 g, 49%). ¹H NMR (DMSO-d₆) δ12.75 (br s, 1H), 7.82 (d, J=8 Hz, 1H), 7.57 (s, 1H), 7.42 (s, 1H), 7.15(d, J=8 Hz, 1H); ESI-MS 158.2 m/z (MH⁺).

Example 3

2,2-Dimethyl-N-o-tolyl-propionamide

To a solution of o-tolylamine (21.4 g, 0.20 mol) and Et₃N (22.3 g, 0.22mol) in CH₂Cl₂ was added 2,2-dimethyl-propionyl chloride (25.3 g, 0.21mol) at 10° C. The mixture was stirred overnight at room temperature,washed with aq. HCl (5%, 80 mL), saturated NaHCO₃ solution and brine,dried over Na₂SO₄ and concentrated under vacuum to give2,2-dimethyl-N-o-tolyl-propionamide (35.0 g, 92%).

2-tert-Butyl-1H-indole

To a solution of 2,2-dimethyl-N-o-tolyl-propionamide (30.0 g, 159 mmol)in dry THF (100 mL) was added dropwise n-BuLi (2.5 M, in hexane, 190 mL)at 15° C. The mixture was stirred overnight at 15° C., cooled in anice-water bath and treated with saturated NH₄Cl solution. The organiclayer was separated and the aqueous layer was extracted with ethylacetate. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated in vacuum. The residue was purified by columnchromatography to give 2-tert-butyl-1H-indole (23.8 g, 88%).

2-tert-Butyl-2,3-dihydro-1H-indole

To a solution of 2-tert-butyl-1H-indole (5.0 g, 29 mmol) in AcOH (20 mL)was added NaBH₄ at 10° C. The mixture was stirred for 20 min at 10° C.,treated dropwise with H₂O under ice cooling, and extracted with ethylacetate. The combined organic layers were dried over anhydrous Na₂SO₄,filtered, and concentrated under vacuum to give a mixture of startingmaterial and 2-tert-butyl-2,3-dihydro-1H-indole (4.9 g), which was useddirectly in the next step.

2-tert-Butyl-6-nitro-2,3-dihydro-1H-indole

To a solution of the mixture of 2-tert-butyl-2,3-dihydro-1H-indole and2-tert-butyl-1H-indole (9.7 g) in H₂SO₄ (98%, 80 mL) was slowly addedKNO₃ (5.6 g, 55.7 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 1 h, carefully poured into cracked ice, basifiedwith Na₂CO₃ to pH-8 and extracted with ethyl acetate. The combinedextracts were washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under vacuum. The residue was purified by columnchromatography to give 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (4.0g, 32% over 2 steps).

2-tert-Butyl-6-nitro-1H-indole

To a solution of 2-tert-butyl-6-nitro-2,3-dihydro-1H-indole (2.0 g, 9.1mmol) in 1,4-dioxane (20 mL) was added DDQ at room temperature. Afterrefluxing for 2.5 h, the mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by columnchromatography to give 2-tert-butyl-6-nitro-1H-indole (1.6 g, 80%).

B-6; 2-tert-Butyl-1H-indol-6-ylamine

To a solution of 2-tert-butyl-6-nitro-1H-indole (1.3 g, 6.0 mmol) inMeOH (10 mL) was added Raney Ni (0.2 g). The mixture was stirred at roomtemperature under H₂ (1 atm) for 3 h. The reaction mixture was filteredand the filtrate was concentrated. The residue was washed with petroleumether to give 2-tert-butyl-1H-indol-6-ylamine (B-6) (1.0 g, 89%). ¹H NMR(DMSO-d₆) δ 10.19 (s, 1H), 6.99 (d, J=8.1 Hz, 1H), 6.46 (s, 1H), 6.25(dd, J=1.8, 8.1 Hz, 1H), 5.79 (d, J=1.8 Hz, 1H), 4.52 (s, 2H), 1.24 (s,9H); ESI-MS 189.1 m/z (MH⁺).

3-Substituted 6-aminoindoles

Example 1

N-(3-Nitro-phenyl)-N′-propylidene-hydrazine

Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirredsuspension of (3-nitro-phenyl)-hydrazine hydrochloride salt (B-4-a)(1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) wasadded to the mixture followed by propionaldehyde (0.7 g, 12 mmol). Afterstirring for 3 h at room temperature, the mixture was poured intoice-water and the resulting precipitate was isolated via filtration,washed with water and dried in air to obtainN-(3-nitro-phenyl)-N′-propylidene-hydrazine, which was used directly inthe next step.

3-Methyl-4-nitro-1H-indole and 3-Methyl-6-nitro-1H-indole

A mixture of N-(3-nitro-phenyl)-N′-propylidene-hydrazine dissolved in85% H₃PO₄ (20 mL) and toluene (20 mL) was heated at 90-100° C. for 2 h.After cooling, toluene was removed under reduced pressure. The resultantoil was basified with 10% NaOH to pH 8. The aqueous layer was extractedwith EtOAc (100 mL×3). The combined organic layers were dried, filteredand concentrated under reduced pressure to afford a mixture of3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole (1.5 g, 86%over two steps), which was used directly in the next step.

B-7; 3-Methyl-1H-indol-6-ylamine

A mixture of 3-methyl-4-nitro-1H-indole and 3-methyl-6-nitro-1H-indole(3 g, 17 mol) and 10% Pd—C (0.5 g) in ethanol (30 mL) was stirredovernight under H₂ (1 atm) at room temperature. Pd—C was filtered offand the filtrate was concentrated under reduced pressure. The residuewas purified by column chromatography to give3-methyl-1H-indol-6-ylamine (B-7) (0.6 g, 24%). ¹H NMR (CDCl₃) δ 7.59(br s, 1H), 7.34 (d, J=8.0 Hz, 1H), 6.77 (s, 1H), 6.64 (s, 1H), 6.57 (m,1H), 3.57 (br s, 2H), 2.28 (s, 3H); ESI-MS 147.2 m/z (MH⁺).

Example 2

6-Nitro-1H-indole-3-carbonitrile

To a solution of 6-nitroindole (4.86 g 30 mmol) in DMF (24.3 mL) andCH₃CN (243 mL) was added dropwise a solution of ClSO₂NCO (5 mL, 57 mmol)in CH₃CN (39 mL) at 0° C. After addition, the reaction was allowed towarm to room temperature and stirred for 2 h. The mixture was pouredinto ice-water, basified with sat. NaHCO₃ solution to pH 7-8 andextracted with ethyl acetate. The organic layer was washed with brine,dried over Na₂SO₄ and concentrated to give6-nitro-1H-indole-3-carbonitrile (4.6 g, 82%).

B-8; 6-Amino-1H-indole-3-carbonitrile

A suspension of 6-nitro-1H-indole-3-carbonitrile (4.6 g, 24.6 mmol) and10% Pd—C (0.46 g) in EtOH (50 mL) was stirred under H₂ (1 atm) at roomtemperature overnight. After filtration, the filtrate was concentratedand the residue was purified by column chromatography (Pet.Ether/EtOAc=3/1) to give 6-amino-1H-indole-3-carbonitrile (B-8) (1 g,99%) as a pink powder. ¹H NMR (DMSO-d₆) δ 11.51 (s, 1H), 7.84 (d, J=2.4Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 6.62 (s, 1H), 6.56 (d, J=8.4 Hz, 1H),5.0 (s, 2H); ESI-MS 157.1 m/z (MH⁺).

Example 3

Dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine

A solution of dimethylamine (25 g, 0.17 mol) and formaldehyde (14.4 mL,0.15 mol) in acetic acid (100 mL) was stirred at 0° C. for 30 min. Tothis solution was added 6-nitro-1H-indole (20 g, 0.12 mol). Afterstirring for 3 days at room temperature, the mixture was poured into 15%aq. NaOH solution (500 mL) at 0° C. The precipitate was collected viafiltration and washed with water to givedimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine (23 g, 87%).

B-9-a; (6-Nitro-1H-indol-3-yl)-acetonitrile

To a mixture of DMF (35 mL) and MeI (74.6 g, 0.53 mol) in water (35 mL)and THF (400 mL) was added dimethyl-(6-nitro-1H-indol-3-ylmethyl)-amine(23 g, 0.105 mol). After the reaction mixture was refluxed for 10 min,potassium cyanide (54.6 g, 0.84 mol) was added and the mixture was keptrefluxing overnight. The mixture was then cooled to room temperature andfiltered. The filtrate was washed with brine (300 mL×3), dried overNa₂SO₄, filtered and concentrated. The residue was purified by columnchromatography to give (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (7.5g, 36%).

B-9; (6-Amino-1H-indol-3-yl)-acetonitrile

A mixture of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (1.5 g, 74.5mml) and 10% Pd—C (300 mg) in EtOH (50 mL) was stirred at roomtemperature under H₂ (1 atm) for 5 h. Pd—C was removed via filtrationand the filtrate was evaporated to give(6-amino-1H-indol-3-yl)-acetonitrile (B-9) (1.1 g, 90%). ¹H NMR(DMSO-d₆) δ 10.4 (br s, 1H), 7.18 (d, J=8.4 Hz, 1H), 6.94 (s, 1H), 6.52(s, 1H), 6.42 (dd, J=8.4, 1.8 Hz, 1H), 4.76 (s, 2H), 3.88 (s, 2H);ESI-MS 172.1 m/z (MH⁺).

Example 4

[2-(6-Nitro-1H-indol-3-yl)-ethyl]-carbamic Acid tert-butyl Ester

To a solution of (6-nitro-1H-indol-3-yl)-acetonitrile (B-9-a) (8.6 g,42.8 mmol) in dry THF (200 mL) was added a solution of 2 Mborane-dimethyl sulfide complex in THF (214 mL. 0.43 mol) at 0° C. Themixture was heated at reflux overnight under nitrogen. The mixture wasthen cooled to room temperature and a solution of (Boc)₂O (14 g, 64.2mmol) and Et₃N (89.0 mL, 0.64 mol) in THF was added. The reactionmixture was kept stirring overnight and then poured into ice-water. Theorganic layer was separated and the aqueous phase was extracted withEtOAc (200×3 mL). The combined organic layers were washed with water andbrine, dried over Na₂SO₄, filtered and concentrated under reducedpressure. The crude was purified by column chromatography to give[2-(6-nitro-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (5 g,38%).

B-10; [2-(6-Amino-1H-indol-3-yl)-ethyl]-carbamic Acid tert-butyl Ester

A mixture of [2-(6-nitro-1H-indol-3-yl)-ethyl]-carbamic acid tert-butylester (5 g, 16.4 mmol) and Raney Ni (1 g) in EtOH (100 mL) was stirredat room temperature under H₂ (1 atm) for 5 h. Raney Ni was filtered offand the filtrate was evaporated under reduced pressure. The crudeproduct was purified by column chromatography to give[2-(6-amino-1H-indol-3-yl)-ethyl]-carbamic acid tert-butyl ester (B-10)(3 g, 67%). ¹H NMR (DMSO-d₆) δ 10.1 (br s, 1H), 7.11 (d, J=8.4 Hz, 1H),6.77-6.73 (m, 2H), 6.46 (d, J=1.5 Hz, 1H), 6.32 (dd, J=8.4, 2.1 Hz, 1H),4.62 (s, 2H), 3.14-3.08 (m, 2H), 2.67-2.62 (m, 2H), 1.35 (s, 9H); ESI-MS275.8 m/z (MH⁺).

Example 5 General Scheme

Specific Example

3-tert-Butyl-6-nitro-1H-indole

To a mixture of 6-nitroindole (1 g, 6.2 mmol), zinc triflate (2.06 g,5.7 mmol) and TBAI (1.7 g, 5.16 mmol) in anhydrous toluene (11 mL) wasadded DIEA (1.47 g, 11.4 mmol) at room temperature under nitrogen. Thereaction mixture was stirred for 10 min at 120° C., followed by additionof t-butyl bromide (0.707 g, 5.16 mmol). The resulting mixture wasstirred for 45 min at 120° C. The solid was filtered off and thefiltrate was concentrated to dryness and purified by columnchromatography on silica gel (Pet.Ether./EtOAc 20:1) to give3-tert-butyl-6-nitro-1H-indole as a yellow solid (0.25 g, 19%). ¹H NMR(CDCl₃) δ 8.32 (d, J=2.1 Hz, 1H), 8.00 (dd, J=2.1, 14.4 Hz, 1H), 7.85(d, J=8.7 Hz, 1H), 7.25 (s, 1H), 1.46 (s, 9H).

B-11; 3-tert-Butyl-1H-indol-6-ylamine

A suspension of 3-tert-butyl-6-nitro-1H-indole (3.0 g, 13.7 mmol) andRaney Ni (0.5 g) in ethanol was stirred at room temperature under H₂ (1atm) for 3 h. The catalyst was filtered off and the filtrate wasconcentrated to dryness. The residue was purified by columnchromatography on silica gel (Pet.Ether./EtOAc 4:1) to give3-tert-butyl-1H-indol-6-ylamine (B-11) (2.0 g, 77.3%) as a gray solid.¹H NMR (CDCl₃): δ 7.58 (m, 2H), 6.73 (d, J=1.2 Hz, 1H), 6.66 (s, 1H),6.57 (dd, J=0.8, 8.6 Hz, 1H), 3.60 (br s, 2H), 1.42 (s, 9H).

Other Examples

B-12; 3-Ethyl-1H-indol-6-ylamine

3-Ethyl-1H-indol-6-ylamine (B-12) was synthesized following the generalscheme above starting from 6-nitroindole and ethyl bromide. Overallyield (42%). HPLC ret. time 1.95 min, 10-99% CH₃CN, 5 min run; ESI-MS161.3 m/z (MH⁺).

B-13; 3-Isopropyl-1H-indol-6-ylamine

3-Isopropyl-1H-indol-6-ylamine (B-13) was synthesized following thegeneral scheme above starting from 6-nitroindole and isopropyl iodide.Overall yield (17%). HPLC ret. time 2.06 min, 10-99% CH₃CN, 5 min run;ESI-MS 175.2 m/z (MH⁺).

B-14; 3-sec-Butyl-1H-indol-6-ylamine

3-sec-Butyl-1H-indol-6-ylamine (B-14) was synthesized following thegeneral scheme above starting from 6-nitroindole and 2-bromobutane.Overall yield (20%). HPLC ret. time 2.32 min, 10-99% CH₃CN, 5 min run;ESI-MS 189.5 m/z (MH⁺).

B-15; 3-Cyclopentyl-1H-indol-6-ylamine

3-Cyclopentyl-1H-indol-6-ylamine (B-15) was synthesized following thegeneral scheme above starting from 6-nitroindole and iodo-cyclopentane.Overall yield (16%). HPLC ret. time 2.39 min, 10-99% CH₃CN, 5 min run;ESI-MS 201.5 m/z (MH⁺).

B-16; 3-(2-Ethoxy-ethyl)-1H-indol-6-ylamine

3-(2-Ethoxy-ethyl)-1H-indol-6-ylamine (B-16) was synthesized followingthe general scheme above starting from 6-nitroindole and1-bromo-2-ethoxy-ethane. Overall yield (15%). HPLC ret. time 1.56 min,10-99% CH₃CN, 5 min run; ESI-MS 205.1 m/z (MH⁺).

B-17; (6-Amino-1H-indol-3-yl)-acetic Acid Ethyl Ester

(6-Amino-1H-indol-3-yl)-acetic acid ethyl ester (B-17) was synthesizedfollowing the general scheme above starting from 6-nitroindole andiodo-acetic acid ethyl ester. Overall yield (24%). HPLC ret. time 0.95min, 10-99% CH₃CN, 5 min run; ESI-MS 219.2 m/z (MH⁺).

4-Substituted 6-aminoindole

2-Methyl-3,5-dinitro-benzoic Acid

To a mixture of HNO₃ (95%, 80 mL) and H₂SO₄ (98%, 80 mL) was slowlyadded 2-methylbenzoic acid (50 g, 0.37 mol) at 0° C. After addition, thereaction mixture was stirred for 1.5 h while keeping the temperaturebelow 30° C., poured into ice-water and stirred for 15 min. Theresulting precipitate was collected via filtration and washed with waterto give 2-methyl-3,5-dinitro-benzoic acid (70 g, 84%).

2-Methyl-3,5-dinitro-benzoic Acid Ethyl Ester

A mixture of 2-methyl-3,5-dinitro-benzoic acid (50 g, 0.22 mol) in SOCl₂(80 mL) was heated at reflux for 4 h and then was concentrated todryness. CH₂Cl₂ (50 mL) and EtOH (80 mL) were added. The mixture wasstirred at room temperature for 1 h, poured into ice-water and extractedwith EtOAc (3×100 mL). The combined extracts were washed with sat.Na₂CO₃ (80 mL), water (2×100 mL) and brine (100 mL), dried over Na₂SO₄and concentrated to dryness to give 2-methyl-3,5-dinitro-benzoic acidethyl ester (50 g, 88%).

2-(2-Dimethylamino-vinyl)-3,5-dinitro-benzoic Acid Ethyl Ester

A mixture of 2-methyl-3,5-dinitro-benzoic acid ethyl ester (35 g, 0.14mol) and dimethoxymethyl-dimethyl-amine (32 g, 0.27 mol) in DMF (200 mL)was heated at 100° C. for 5 h. The mixture was poured into ice-water.The precipitate was collected via filtration and washed with water togive 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethyl ester(11.3 g, 48%).

B-18; 6-Amino-1H-indole-4-carboxylic Acid Ethyl Ester

A mixture of 2-(2-dimethylamino-vinyl)-3,5-dinitro-benzoic acid ethylester (11.3 g, 0.037 mol) and SnCl₂ (83 g. 0.37 mol) in ethanol washeated at reflux for 4 h. The mixture was concentrated to dryness andthe residue was poured into water and basified with sat. Na₂CO₃ solutionto pH 8. The precipitate was filtered off and the filtrate was extractedwith ethyl acetate (3×100 mL). The combined extracts were washed withwater (2×100 mL) and brine (150 mL), dried over Na₂SO₄ and concentratedto dryness. The residue was purified by column chromatography on silicagel to give 6-amino-1H-indole-4-carboxylic acid ethyl ester (B-18) (3 g,40%). ¹H NMR (DMSO-d₆) δ 10.76 (br s, 1H), 7.11-7.14 (m, 2H), 6.81-6.82(m, 1H), 6.67-6.68 (m, 1H), 4.94 (br s, 2H), 4.32-4.25 (q, J=7.2 Hz,2H), 1.35-1.31 (t, J=7.2, 3H). ESI-MS 205.0 m/z (MH⁺).

5-Substituted 6-aminoindoles

Example 1 General Scheme

Specific Example

1-Fluoro-5-methyl-2,4-dinitro-benzene

To a stirred solution of HNO₃ (60 mL) and H₂SO₄ (80 mL), cooled in anice bath, was added 1-fluoro-3-methyl-benzene (27.5 g, 25 mmol) at sucha rate that the temperature did not rise over 35° C. The mixture wasallowed to stir for 30 min at room temperature and poured into ice water(500 mL). The resulting precipitate (a mixture of the desired productand 1-fluoro-3-methyl-2,4-dinitro-benzene, approx. 7:3) was collectedvia filtration and purified by recrystallization from 50 mL isopropylether to give 1-fluoro-5-methyl-2,4-dinitro-benzene as a white solid (18g, 36%).

[2-(5-Fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine

A mixture of 1-fluoro-5-methyl-2,4-dinitro-benzene (10 g, 50 mmol),dimethoxymethyl-dimethylamine (11.9 g, 100 mmol) and DMF (50 mL) washeated at 100° C. for 4 h. The solution was cooled and poured intowater. The red precipitate was collected via filtration, washed withwater adequately and dried to give[2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine (8 g, 63%).

B-20; 5-Fluoro-1H-indol-6-ylamine

A suspension of [2-(5-fluoro-2,4-dinitro-phenyl)-vinyl]-dimethyl-amine(8 g, 31.4 mmol) and Raney Ni (8 g) in EtOH (80 mL) was stirred under H₂(40 psi) at room temperature for 1 h. After filtration, the filtrate wasconcentrated and the residue was purified by chromatography(Pet.Ether/EtOAc=5/1) to give 5-fluoro-1H-indol-6-ylamine (B-20) as abrown solid (1 g, 16%). ¹H NMR (DMSO-d₆) δ 10.56 (br s, 1H), 7.07 (d,J=12 Hz, 1H), 7.02 (m, 1H), 6.71 (d, J=8 Hz, 1H), 6.17 (s, 1H), 3.91 (brs, 2H); ESI-MS 150.1 m/z (MH⁺).

Other Examples

B-21; 5-Chloro-1H-indol-6-ylamine

5-Chloro-1H-indol-6-ylamine (B-21) was synthesized following the generalscheme above starting from 1-chloro-3-methyl-benzene. Overall yield(7%). ¹H NMR (CDCl₃) 6.7.85 (br s, 1H), 7.52 (s, 1H), 7.03 (s, 1H), 6.79(s, 1H), 6.34 (s, 1H), 3.91 (br s, 2H); ESI-MS 166.0 m/z (MH⁺).

B-22; 5-Trifluoromethyl-1H-indol-6-ylamine

5-Trifluoromethyl-1H-indol-6-ylamine (B-22) was synthesized followingthe general scheme above starting from1-methyl-3-trifluoromethyl-benzene. Overall yield (2%). ¹H NMR (DMSO-d₆)10.79 (br s, 1H), 7.55 (s, 1H), 7.12 (s, 1H), 6.78 (s, 1H), 6.27 (s,1H), 4.92 (s, 2H); ESI-MS 200.8 m/z (MH⁺).

Example 2

1-Benzenesulfonyl-2,3-dihydro-1H-indole

To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24 g, 136 mmol)and 2,3-dihydro-1H-indole (14.7 g, 124 mmol) in CH₂Cl₂ (200 mL) wasadded dropwise Et₃N (19 g, 186 mmol) in an ice-water bath. Afteraddition, the mixture was stirred at room temperature overnight, washedwith water, dried over Na₂SO₄ and concentrated to dryness under reducedpressure to provide 1-benzenesulfonyl-2,3-dihydro-1H-indole (30.9 g,96%).

1-(1-Benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone

To a stirring suspension of AlCl₃ (144 g, 1.08 mol) in CH₂Cl₂ (1070 mL)was added acetic anhydride (54 mL). The mixture was stirred for 15minutes. A solution of 1-benzenesulfonyl-2,3-dihydro-1H-indole (46.9 g,0.18 mol) in CH₂Cl₂ (1070 mL) was added dropwise. The mixture wasstirred for 5 h and quenched by the slow addition of crushed ice. Theorganic layer was separated and the aqueous layer was extracted withCH₂Cl₂. The combined organic layers were washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄ and concentrated under vacuum toyield 1-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone (42.6 g,79

1-Benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole

To magnetically stirred TFA (1600 mL) was added at 0° C. sodiumborohydride (64 g, 1.69 mol) over 1 h. To this mixture was addeddropwise a solution of1-(1-benzenesulfonyl-2,3-dihydro-1H-indol-5-yl)-ethanone (40 g, 0.13mol) in TFA (700 mL) over 1 h. The mixture was stirred overnight at 25°C., diluted with H₂O (1600 ml), and basified with sodium hydroxidepellets at 0° C. The organic layer was separated and the aqueous layerwas extracted with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by column chromatography on silica gel to give1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (16.2 g, 43%).

5-Ethyl-2,3-dihydro-1H-indole

A mixture of 1-benzenesulfonyl-5-ethyl-2,3-dihydro-1H-indole (15 g, 0.05mol) in HBr (48%, 162 mL) was heated at reflux for 6 h. The mixture wasbasified with sat. NaOH solution to pH 9 and extracted with ethylacetate. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel to give 5-ethyl-2,3-dihydro-1H-indole (2.5g, 32%).

5-Ethyl-6-nitro-2,3-dihydro-1H-indole

To a solution of 5-ethyl-2,3-dihydro-1H-indole (2.5 g, 17 mmol) in H₂SO₄(98%, 20 mL) was slowly added KNO₃ (1.7 g, 17 mmol) at 0° C. Afteraddition, the mixture was stirred at 0-10° C. for 10 min, carefullypoured into ice, basified with NaOH solution to pH 9 and extracted withethyl acetate. The combined extracts were washed with brine, dried overNa₂SO₄ and concentrated to dryness. The residue was purified by columnchromatography on silica gel to give5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 58%).

5-Ethyl-6-nitro-1H-indole

To a solution of 5-ethyl-6-nitro-2,3-dihydro-1H-indole (1.9 g, 9.9 mmol)in CH₂Cl₂ (30 mL) was added MnO₂ (4 g, 46 mmol). The mixture was stirredat room temperature for 8 h. The solid was filtered off and the filtratewas concentrated to dryness to give crude 5-ethyl-6-nitro-1H-indole (1.9g, quant.).

B-23; 5-Ethyl-1H-indol-6-ylamine

A suspension of 5-ethyl-6-nitro-1H-indole (1.9 g, 10 mmol) and Raney Ni(1 g) was stirred under H₂ (1 atm) at room temperature for 2 h. Thecatalyst was filtered off and the filtrate was concentrated to dryness.The residue was purified by column chromatography on silica gel to give5-ethyl-1H-indol-6-ylamine (B-23) (760 mg, 48%). ¹H NMR (CDCl₃) δ 7.90(br s, 1H), 7.41 (s, 1H), 7.00 (s, 1H), 6.78 (s, 2H), 6.39 (s, 1H), 3.39(br s, 2H), 2.63 (q, J=7.2 Hz, 2H), 1.29 (t, J=6.9 Hz, 3H); ESI-MS 161.1m/z (MH⁺).

Example 3

2-Bromo-4-tert-butyl-phenylamine

To a solution of 4-tert-butyl-phenylamine (447 g, 3 mol) in DMF (500 mL)was added dropwise NBS (531 g, 3 mol) in DMF (500 mL) at roomtemperature. Upon completion, the reaction mixture was diluted withwater and extracted with EtOAc. The organic layer was washed with water,brine, dried over Na₂SO₄ and concentrated. The crude product wasdirectly used in the next step without further purification.

2-Bromo-4-tert-butyl-5-nitro-phenylamine

2-Bromo-4-tert-butyl-phenylamine (162 g, 0.71 mol) was added dropwise toH₂SO₄ (410 mL) at room temperature to yield a clear solution. This clearsolution was then cooled down to −5 to −10° C. A solution of KNO₃ (82.5g, 0.82 mol) in H₂SO₄ (410 mL) was added dropwise while the temperaturewas maintained between −5 to −10° C. Upon completion, the reactionmixture was poured into ice/water and extracted with EtOAc. The combinedorganic layers were washed with 5% Na₂CO₃ and brine, dried over Na₂SO₄and concentrated. The residue was purified by a column chromatography(EtOAc/petroleum ether 1/10) to give2-bromo-4-tert-butyl-5-nitro-phenylamine as a yellow solid (152 g, 78%).

4-tert-Butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine

To a mixture of 2-bromo-4-tert-butyl-5-nitro-phenylamine (27.3 g, 100mmol) in toluene (200 mL) and water (100 mL) was added Et₃N (27.9 mL,200 mmol), Pd(PPh₃)₂Cl₂ (2.11 g, 3 mmol), CuI (950 mg, 0.5 mmol) andtrimethylsilyl acetylene (21.2 mL, 150 mmol) under a nitrogenatmosphere. The reaction mixture was heated at 70° C. in a sealedpressure flask for 2.5 h., cooled down to room temperature and filteredthrough a short plug of Celite. The filter cake was washed with EtOAc.The combined filtrate was washed with 5% NH₄OH solution and water, driedover Na₂SO₄ and concentrated. The crude product was purified by columnchromatography (0-10% EtOAc/petroleum ether) to provide4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine as a brownviscous liquid (25 g, 81%).

5-tert-Butyl-6-nitro-1H-indole

To a solution of4-tert-butyl-5-nitro-2-trimethylsilanylethynyl-phenylamine (25 g, 86mmol) in DMF (100 mL) was added CuI (8.2 g, 43 mmol) under a nitrogenatmosphere. The mixture was heated at 135° C. in a sealed pressure flaskovernight, cooled down to room temperature and filtered through a shortplug of Celite. The filter cake was washed with EtOAc. The combinedfiltrate was washed with water, dried over Na₂SO₄ and concentrated. Thecrude product was purified by column chromatography (10-20%EtOAc/Hexane) to provide 5-tert-butyl-6-nitro-1H-indole as a yellowsolid (12.9 g, 69%).

B-24; 5-tert-Butyl-1H-indol-6-ylamine

Raney Ni (3 g) was added to 5-tert-butyl-6-nitro-1H-indole (14.7 g, 67mmol) in methanol (100 mL). The mixture was stirred under hydrogen (1atm) at 30° C. for 3 h. The catalyst was filtered off. The filtrate wasdried over Na₂SO₄ and concentrated. The crude dark brown viscous oil waspurified by column chromatography (10-20% EtOAc/petroleum ether) to give5-tert-butyl-1H-indol-6-ylamine (B-24) as a gray solid (11 g, 87%). ¹HNMR (300 MHz, DMSO-d₆) δ 10.3 (br s, 1H), 7.2 (s, 1H), 6.9 (m, 1H), 6.6(s, 1H), 6.1 (m, 1H), 4.4 (br s, 2H), 1.3 (s, 9H).

Example 4

5-Methyl-2,4-dinitro-benzoic Acid

To a mixture of HNO₃ (95%, 80 mL) and H₂SO₄ (98%, 80 mL) was slowlyadded 3-methylbenzoic acid (50 g, 0.37 mol) at 0° C. After addition, themixture was stirred for 1.5 h while maintaining the temperature below30° C. The mixture was poured into ice-water and stirred for 15 min. Theprecipitate was collected via filtration and washed with water to give amixture of 3-methyl-2,6-dinitro-benzoic acid and5-methyl-2,4-dinitro-benzoic acid (70 g, 84%). To a solution of thismixture in EtOH (150 mL) was added dropwise SOCl₂ (53.5 g, 0.45 mol).The mixture was heated at reflux for 2 h and concentrated to drynessunder reduced pressure. The residue was dissolved in EtOAc (100 mL) andextracted with 10% Na₂CO₃ solution (120 mL). The organic layer was foundto contain 5-methyl-2,4-dinitro-benzoic acid ethyl ester while theaqueous layer contained 3-methyl-2,6-dinitro-benzoic acid. The organiclayer was washed with brine (50 mL), dried over Na₂SO₄ and concentratedto dryness to provide 5-methyl-2,4-dinitro-benzoic acid ethyl ester (20g, 20%).

5-(2-Dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester

A mixture of 5-methyl-2,4-dinitro-benzoic acid ethyl ester (39 g, 0.15mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL)was heated at 100° C. for 5 h. The mixture was poured into ice water.The precipitate was collected via filtration and washed with water toafford 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethyl ester(15 g, 28%).

B-25; 6-Amino-1H-indole-5-carboxylic acid ethyl ester

A mixture of 5-(2-dimethylamino-vinyl)-2,4-dinitro-benzoic acid ethylester (15 g, 0.05 mol) and Raney Ni (5 g) in EtOH (500 mL) was stirredunder H₂ (50 psi) at room temperature for 2 h. The catalyst was filteredoff and the filtrate was concentrated to dryness. The residue waspurified by column chromatography on silica gel to give6-amino-1H-indole-5-carboxylic acid ethyl ester (B-25) (3 g, 30%). ¹HNMR (DMSO-d₆) δ 10.68 (s, 1H), 7.99 (s, 1H), 7.01-7.06 (m, 1H), 6.62 (s,1H), 6.27-6.28 (m, 1H), 6.16 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 1.32-1.27(t, J=7.2 Hz, 3H).

Example 5

1-(2,3-Dihydro-indol-1-yl)-ethanone

To a suspension of NaHCO₃ (504 g, 6.0 mol) and 2,3-dihydro-1H-indole (60g, 0.5 mol) in CH₂Cl₂ (600 mL) cooled in an ice-water bath, was addeddropwise acetyl chloride (78.5 g, 1.0 mol). The mixture was stirred atroom temperature for 2 h. The solid was filtered off and the filtratewas concentrated to give 1-(2,3-dihydro-indol-1-yl)-ethanone (82 g,100%).

1-(5-Bromo-2,3-dihydro-indol-1-yl)-ethanone

To a solution of 1-(2,3-dihydro-indol-1-yl)-ethanone (58.0 g, 0.36 mol)in acetic acid (3000 mL) was added Br₂ (87.0 g, 0.54 mol) at 10° C. Themixture was stirred at room temperature for 4 h. The precipitate wascollected via filtration to give crude1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g, 96%), which was useddirectly in the next step.

5-Bromo-2,3-dihydro-1H-indole

A mixture of crude 1-(5-bromo-2,3-dihydro-indol-1-yl)-ethanone (100 g,0.34 mol) in HCl (20%, 1200 mL) was heated at reflux for 6 h. Themixture was basified with Na₂CO₃ to pH 8.5-10 and then extracted withethyl acetate. The combined organic layers were washed with brine, driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by column chromatography on silica gel to give5-bromo-2,3-dihydro-1H-indole (37 g, 55%).

5-Bromo-6-nitro-2,3-dihydro-1H-indole

To a solution of 5-bromo-2,3-dihydro-1H-indole (45 g, 0.227 mol) inH₂SO₄ (98%, 200 mL) was slowly added KNO₃ (23.5 g, 0.23 mol) at 0° C.After addition, the mixture was stirred at 0-10° C. for 4 h, carefullypoured into ice, basified with Na₂CO₃ to pH 8 and extracted with ethylacetate. The combined organic extracts were washed with brine, driedover Na₂SO₄ and concentrated to dryness. The residue was purified bycolumn chromatography on silica gel to give5-bromo-6-nitro-2,3-dihydro-1H-indole (42 g, 76%).

5-Bromo-6-nitro-1H-indole

To a solution of 5-bromo-6-nitro-2,3-dihydro-1H-indole (20 g, 82.3 mmol)in 1,4-dioxane (400 mL) was added DDQ (30 g, 0.13 mol). The mixture wasstirred at 80° C. for 2 h. The solid was filtered off and the filtratewas concentrated to dryness. The residue was purified by columnchromatography on silica gel to afford 5-bromo-6-nitro-1H-indole (7.5 g,38%).

B-27; 5-Bromo-1H-indol-6-ylamine

A mixture of 5-bromo-6-nitro-1H-indole (7.5 g, 31.1 mmol) and Raney Ni(1 g) in ethanol was stirred under H₂ (1 atm) at room temperature for 2h. The catalyst was filtered off and the filtrate was concentrated todryness. The residue was purified by column chromatography on silica gelto give 5-bromo-1H-indol-6-ylamine (B-27) (2 g, 30%). ¹H NMR (DMSO-d₆) δ10.6 (s, 1H), 7.49 (s, 1H), 6.79-7.02 (m, 1H), 6.79 (s, 1H), 6.14-6.16(m, 1H), 4.81 (s, 2H).

7-Substituted 6-aminoindole

3-Methyl-2,6-dinitro-benzoic acid

To a mixture of HNO₃ (95%, 80 mL) and H₂SO₄ (98%, 80 mL) was slowlyadded 3-methylbenzoic acid (50 g, 0.37 mol) at 0° C. After addition, themixture was stirred for 1.5 h while maintaining the temperature below30° C. The mixture was poured into ice-water and stirred for 15 min. Theprecipitate was collected via filtration and washed with water to give amixture of 3-methyl-2,6-dinitro-benzoic acid and5-methyl-2,4-dinitro-benzoic acid (70 g, 84%).

To a solution of this mixture in EtOH (150 mL) was added dropwise SOCl₂(53.5 g, 0.45 mol). The mixture was heated to reflux for 2 h andconcentrated to dryness under reduced pressure. The residue wasdissolved in EtOAc (100 mL) and extracted with 10% Na₂CO₃ solution (120mL). The organic layer was found to contain 5-methyl-2,4-dinitro-benzoicacid ethyl ester. The aqueous layer was acidified with HCl to pH 2˜3 andthe resulting precipitate was collected via filtration, washed withwater and dried in air to give 3-methyl-2,6-dinitro-benzoic acid (39 g,47

3-Methyl-2,6-dinitro-benzoic acid ethyl ester

A mixture of 3-methyl-2,6-dinitro-benzoic acid (39 g, 0.15 mol) andSOCl₂ (80 mL) was heated at reflux for 4 h. The excess SOCl₂ was removedunder reduced pressure and the residue was added dropwise to a solutionof EtOH (100 mL) and Et₃N (50 mL). The mixture was stirred at 20° C. for1 h and concentrated to dryness. The residue was dissolved in EtOAc (100mL), washed with Na₂CO₃ (10%, 40 mL×2), water (50 mL×2) and brine (50mL), dried over Na₂SO₄ and concentrated to give3-methyl-2,6-dinitro-benzoic acid ethyl ester (20 g, 53%).

3-(2-Dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester

A mixture of 3-methyl-2,6-dinitro-benzoic acid ethyl ester (35 g, 0.14mol) and dimethoxymethyl-dimethylamine (32 g, 0.27 mol) in DMF (200 mL)was heated at 100° C. for 5 h. The mixture was poured into ice water andthe precipitate was collected via filtration and washed with water togive 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethyl ester (25g, 58%).

B-19; 6-Amino-1H-indole-7-carboxylic acid ethyl ester

A mixture of 3-(2-dimethylamino-vinyl)-2,6-dinitro-benzoic acid ethylester (30 g, 0.097 mol) and Raney Ni (10 g) in EtOH (1000 mL) wasstirred under H₂ (50 psi) for 2 h. The catalyst was filtered off, andthe filtrate was concentrated to dryness. The residue was purified bycolumn chromatography on silica gel to give6-amino-1H-indole-7-carboxylic acid ethyl ester (B-19) as an off-whitesolid (3.2 g, 16%). ¹H NMR (DMSO-d₆) δ 10.38 (s, 1H), 7.44-7.41 (d,J=8.7 Hz, 1H), 6.98 (t, 1H), 6.65 (s, 2H), 6.50-6.46 (m, 1H), 6.27-6.26(m, 1H), 4.43-4.36 (q, J=7.2 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H).

Phenols

Example 1

2-tert-Butyl-5-nitroaniline

To a cooled solution of sulfuric acid (90%, 50 mL) was added dropwise2-tert-butyl-phenylamine (4.5 g, 30 mmol) at 0° C. Potassium nitrate(4.5 g, 45 mmol) was added in portions at 0° C. The reaction mixture wasstirred at 0-5° C. for 5 min, poured into ice-water and then extractedwith EtOAc three times. The combined organic layers were washed withbrine and dried over Na₂SO₄. After removal of solvent, the residue waspurified by recrystallization using 70% EtOH—H₂O to give2-tert-butyl-5-nitroaniline (3.7 g, 64%). ¹H NMR (400 MHz, CDCl₃) δ 7.56(dd, J=8.7, 2.4 Hz, 1H), 7.48 (d, J=2.4 Hz, 1H), 7.36 (d, J=8.7 Hz, 1H),4.17 (s, 2H), 1.46 (s, 9H); HPLC ret. time 3.27 min, 10-99% CH₃CN, 5 minrun; ESI-MS 195.3 m/z (MH⁺).

C-1-a; 2-tert-Butyl-5-nitrophenol

To a mixture of 2-tert-butyl-5-nitroaniline (1.94 g, 10 mmol) in 40 mLof 15% H₂SO₄ was added dropwise a solution of NaNO₂ (763 mg, 11.0 mmol)in water (3 mL) at 0° C. The resulting mixture was stirred at 0-5° C.for 5 min. Excess NaNO₂ was neutralized with urea, then 5 mL ofH₂SO₄—H₂O (v/v 1:2) was added and the mixture was refluxed for 5 min.Three additional 5 mL aliquots of H₂SO₄—H₂O (v/v 1:2) were added whileheating at reflux. The reaction mixture was cooled to room temperatureand extracted with EtOAc twice. The combined organic layers were washedwith brine and dried over MgSO₄. After removal of solvent, the residuewas purified by column chromatography (0-10% EtOAc-Hexane) to give2-tert-butyl-5-nitrophenol (C-1-a) (1.2 g, 62%). ¹H NMR (400 MHz, CDCl₃)δ 7.76 (dd, J=8.6, 2.2 Hz, 1H), 7.58 (d, J=2.1 Hz, 1H), 7.43 (d, J=8.6Hz, 1H), 5.41 (s, 1H), 1.45 (s, 9H); HPLC ret. time 3.46 min, 10-99%CH₃CN, 5 min run.

C-1; 2-tert-Butyl-5-aminophenol. To a refluxing solution of2-tert-butyl-5-nitrophenol (C-1-a) (196 mg, 1.0 mmol) in EtOH (10 mL)was added ammonium formate (200 mg, 3.1 mmol), followed by 140 mg of 10%Pd—C. The reaction mixture was refluxed for additional 30 min, cooled toroom temperature and filtered through a plug of Celite. The filtrate wasconcentrated to dryness and purified by column chromatography (20-30%EtOAc-Hexane) to give 2-tert-butyl-5-aminophenol (C-1) (144 mg, 87%). ¹HNMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.04 (d,J=2.3 Hz, 1H), 5.93 (dd, J=8.2, 2.3 Hz, 1H), 4.67 (s, 2H), 1.26 (s, 9H);HPLC ret. time 2.26 min, 10-99% CH₃CN, 5 min run; ESI-MS 166.1 m/z(MH⁺).

Example 2 General Scheme

Specific Example

1-tert-Butyl-2-methoxy-4-nitrobenzene

To a mixture of 2-tert-butyl-5-nitrophenol (C-1-a) (100 mg, 0.52 mmol)and K₂CO₃ (86 mg, 0.62 mmol) in DMF (2 mL) was added CH₃I (40 uL, 0.62mmol). The reaction mixture was stirred at room temperature for 2 h,diluted with water and extracted with EtOAc. The combined organic layerswere washed with brine and dried over MgSO₄. After filtration, thefiltrate was evaporated to dryness to give1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg, 76%) that was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (t, J=4.3 Hz, 1H),7.70 (d, J=2.3 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 3.94 (s, 3H), 1.39 (s,9H).

C-2; 4-tert-Butyl-3-methoxyaniline

To a refluxing solution of 1-tert-butyl-2-methoxy-4-nitrobenzene (82 mg,0.4 mmol) in EtOH (2 mL) was added potassium formate (300 mg, 3.6 mmol)in water (1 mL), followed by 10% Pd—C (15 mg). The reaction mixture wasrefluxed for additional 60 min, cooled to room temperature and filteredthrough Celite. The filtrate was concentrated to dryness to give4-tert-butyl-3-methoxyaniline (C-2) (52 mg, 72%) that was used withoutfurther purification. HPLC ret. time 2.29 min, 10-99% CH₃CN, 5 min run;ESI-MS 180.0 m/z (MH⁺).

Other Examples

C-3; 3-(2-Ethoxyethoxy)-4-tert-butylbenzenamine

3-(2-Ethoxyethoxy)-4-tert-butylbenzenamine (C-3) was synthesizedfollowing the general scheme above starting from2-tert-butyl-5-nitrophenol (C-1-a) and 1-bromo-2-ethoxyethane. ¹H NMR(400 MHz, CDCl₃) δ 6.97 (d, J=7.9 Hz, 1H), 6.17 (s, 1H), 6.14 (d, J=2.3Hz, 1H), 4.00 (t, J=5.2 Hz, 2H), 3.76 (t, J=5.2 Hz, 2H), 3.53 (q, J=7.0Hz, 2H), 1.27 (s, 9H), 1.16 (t, J=7.0 Hz, 3H); HPLC ret. time 2.55 min,10-99% CH₃CN, 5 min run; ESI-MS 238.3 m/z (MH⁺).

C-4; 2-(2-tert-Butyl-5-aminophenoxy)ethanol

2-(2-tert-Butyl-5-aminophenoxy)ethanol (C-4) was synthesized followingthe general scheme above starting from 2-tert-butyl-5-nitrophenol(C-1-a) and 2-bromoethanol. HPLC ret. time 2.08 min, 10-99% CH₃CN, 5 minrun; ESI-MS 210.3 m/z (MH⁺).

Example 3

N-(3-Hydroxy-phenyl)-acetamide and acetic acid 3-formylamino-phenylester

To a well stirred suspension of 3-amino-phenol (50 g, 0.46 mol) andNaHCO₃ (193.2 g, 2.3 mol) in chloroform (1 L) was added dropwisechloroacetyl chloride (46.9 g, 0.6 mol) over a period of 30 min at 0° C.After the addition was complete, the reaction mixture was refluxedovernight and then cooled to room temperature. The excess NaHCO₃ wasremoved via filtration. The filtrate was poured into water and extractedwith EtOAc (300×3 mL). The combined organic layers were washed withbrine (500 mL), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give a mixture of N-(3-hydroxy-phenyl)-acetamide andacetic acid 3-formylamino-phenyl ester (35 g, 4:1 by NMR analysis). Themixture was used directly in the next step.

N-[3-(3-Methyl-but-3-enyloxy)-phenyl]-acetamide

A suspension of the mixture of N-(3-hydroxy-phenyl)-acetamide and aceticacid 3-formylamino-phenyl ester (18.12 g, 0.12 mol),3-methyl-but-3-en-1-ol (8.6 g, 0.1 mol), DEAD (87 g, 0.2 mol) and Ph₃P(31.44 g, 0.12 mol) in benzene (250 mL) was heated at reflux overnightand then cooled to room temperature. The reaction mixture was pouredinto water and the organic layer was separated. The aqueous phase wasextracted with EtOAc (300×3 mL). The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by column chromatography to giveN-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (11 g, 52%).

N-(4,4-Dimethyl-chroman-7-yl)-acetamide

A mixture of N-[3-(3-methyl-but-3-enyloxy)-phenyl]-acetamide (2.5 g,11.4 mmol) and AlCl₃ (4.52 g, 34.3 mmol) in fluoro-benzene (50 mL) washeated at reflux overnight. After cooling, the reaction mixture waspoured into water. The organic layer was separated and the aqueous phasewas extracted with EtOAc (40×3 mL). The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated undervacuum. The residue was purified by column chromatography to giveN-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 54%).

C-5; 3,4-Dihydro-4,4-dimethyl-2H-chromen-7-amine

A mixture of N-(4,4-dimethyl-chroman-7-yl)-acetamide (1.35 g, 6.2 mmol)in 20% HCl solution (30 mL) was heated at reflux for 3 h and then cooledto room temperature. The reaction mixture was basified with 10% aq. NaOHto pH 8 and extracted with EtOAc (30×3 mL). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentrated togive 3,4-dihydro-4,4-dimethyl-2H-chromen-7-amine (C-5) (1 g, 92%). ¹HNMR (DMSO-d₆) δ 6.87 (d, J=8.4 Hz, 1H), 6.07 (dd, J=8.4, 2.4 Hz, 1H),5.87 (d, J=2.4 Hz, 1H), 4.75 (s, 2H), 3.99 (t, J=5.4 Hz, 2H), 1.64 (t,J=5.1 Hz, 2H), 1.15 (s, 6H); ESI-MS 178.1 m/z (MH⁺).

Example 4 General Scheme

Specific Example

2-tert-Butyl-4-fluorophenol

4-Fluorophenol (5 g, 45 mmol) and tert-butanol (5.9 mL, 63 mmol) weredissolved in CH₂Cl₂ (80 mL) and treated with concentrated sulfuric acid(98%, 3 mL). The mixture was stirred at room temperature overnight. Theorganic layer was washed with water, neutralized with NaHCO₃, dried overMgSO₄ and concentrated. The residue was purified by columnchromatography (5-15% EtOAc-Hexane) to give 2-tert-butyl-4-fluorophenol(3.12 g, 42%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 6.89 (dd,J=11.1, 3.1 Hz, 1H), 6.84-6.79 (m, 1H), 6.74 (dd, J=8.7, 5.3 Hz, 1H),1.33 (s, 9H).

2-tert-Butyl-4-fluorophenyl methyl carbonate

To a solution of 2-tert-butyl-4-fluorophenol (2.63 g, 15.7 mmol) andNEt₃ (3.13 mL, 22.5 mmol) in dioxane (45 mL) was added methylchloroformate (1.27 mL, 16.5 mmol). The mixture was stirred at roomtemperature for 1 h. The precipitate was removed via filtration. Thefiltrate was then diluted with water and extracted with ether. The etherextract was washed with water and dried over MgSO₄. After removal ofsolvent, the residue was purified by column chromatography to give2-tert-butyl-4-fluorophenyl methyl carbonate (2.08 g, 59%). ¹H NMR (400MHz, DMSO-d₆) δ 7.24 (dd, J=8.8, 5.4 Hz, 1H), 7.17-7.10 (m, 2H), 3.86(s, 3H), 1.29 (s, 9H).

2-tert-Butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a) and2-tert-butyl-4-fluoro-6-nitrophenyl methyl carbonate (C-6-a)

To a solution of 2-tert-butyl-4-fluorophenyl methyl carbonate (1.81 g, 8mmol) in H₂SO₄ (98%, 1 mL) was added slowly a cooled mixture of H₂SO₄ (1mL) and HNO₃ (1 mL) at 0° C. The mixture was stirred for 2 h whilewarming to room temperature, poured into ice and extracted with diethylether. The ether extract was washed with brine, dried over MgSO₄ andconcentrated. The residue was purified by column chromatography (0-10%EtOAc-Hexane) to give 2-tert-butyl-4-fluoro-5-nitrophenyl methylcarbonate (C-7-a) (1.2 g, 55%) and 2-tert-butyl-4-fluoro-6-nitrophenylmethyl carbonate (C-6-a) (270 mg, 12%).2-tert-Butyl-4-fluoro-5-nitrophenyl methyl carbonate (C-7-a): ¹H NMR(400 MHz, DMSO-d₆) δ 8.24 (d, J=7.1 Hz, 1H), 7.55 (d, J=13.4 Hz, 1H),3.90 (s, 3H), 1.32 (s, 9H). 2-tert-butyl-4-fluoro-6-nitrophenyl methylcarbonate (C-6-a): ¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (dd, J=7.6, 3.1 Hz,1H), 7.69 (dd, J=10.1, 3.1 Hz, 1H), 3.91 (s, 3H), 1.35 (s, 9H).

2-tert-Butyl-4-fluoro-5-nitrophenol

To a solution of 2-tert-butyl-4-fluoro-5-nitrophenyl methyl carbonate(C-7-a) (1.08 g, 4 mmol) in CH₂Cl₂ (40 mL) was added piperidine (3.94mL, 10 mmol). The mixture was stirred at room temperature for 1 h andextracted with 1N NaOH (3×). The aqueous layer was acidified with 1N HCland extracted with diethyl ether. The ether extract was washed withbrine, dried (MgSO₄) and concentrated to give2-tert-butyl-4-fluoro-5-nitrophenol (530 mg, 62%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.40 (s, 1H), 7.49 (d, J=6.8 Hz, 1H), 7.25 (d, J=13.7 Hz,1H), 1.36 (s, 9H).

C-7; 2-tert-Butyl-5-amino-4-fluorophenol

To a refluxing solution of 2-tert-butyl-4-fluoro-5-nitrophenol (400 mg,1.88 mmol) and ammonium formate (400 mg, 6.1 mmol) in EtOH (20 mL) wasadded 5% Pd—C (260 mg). The mixture was refluxed for additional 1 h,cooled and filtered through Celite. The solvent was removed byevaporation to give 2-tert-butyl-5-amino-4-fluorophenol (C-7) (550 mg,83%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (br s, 1H), 6.66 (d, J=13.7 Hz,1H), 6.22 (d, J=8.5 Hz, 1H), 4.74 (br s, 2H), 1.26 (s, 9H); HPLC ret.time 2.58 min, 10-99% CH₃CN, 5 min run; ESI-MS 184.0 m/z (MH⁺).

Other Examples

C-10; 2-tert-Butyl-5-amino-4-chlorophenol

2-tert-Butyl-5-amino-4-chlorophenol (C-10) was synthesized following thegeneral scheme above starting from 4-chlorophenol and tert-butanol.Overall yield (6%). HPLC ret. time 3.07 min, 10-99% CH₃CN, 5 min run;ESI-MS 200.2 m/z (MH⁺).

C-13; 5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclohexyl)phenol (C-13) was synthesizedfollowing the general scheme above starting from 4-fluorophenol and1-methylcyclohexanol. Overall yield (3%). HPLC ret. time 3.00 min,10-99% CH₃CN, 5 min run; ESI-MS 224.2 m/z (MH⁺).

C-19; 5-Amino-2-(3-ethylpentan-3-yl)-4-fluoro-phenol

5-Amino-2-(3-ethylpentan-3-yl)-4-fluoro-phenol (C-19) was synthesizedfollowing the general scheme above starting from 4-fluorophenol and3-ethyl-3-pentanol. Overall yield (1%).

C-20; 2-Admantyl-5-amino-4-fluoro-phenol

2-Admantyl-5-amino-4-fluoro-phenol (C-20) was synthesized following thegeneral scheme above starting from 4-fluorophenol and adamantan-1-ol.

C-21; 5-Amino-4-fluoro-2-(1-methylcycloheptyl)phenol

5-Amino-4-fluoro-2-(1-methylcycloheptyl)phenol (C-21) was synthesizedfollowing the general scheme above starting from 4-fluorophenol and1-methyl-cycloheptanol.

C-22; 5-Amino-4-fluoro-2-(1-methylcyclooctyl)phenol

5-Amino-4-fluoro-2-(1-methylcyclooctyl)phenol (C-22) was synthesizedfollowing the general scheme above starting from 4-fluorophenol and1-methyl-cyclooctanol.

C-23; 5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol

5-Amino-2-(3-ethyl-2,2-dimethylpentan-3-yl)-4-fluoro-phenol (C-23) wassynthesized following the general scheme above starting from4-fluorophenol and 3-ethyl-2,2-dimethyl-pentan-3-ol.

Example 5

C-6; 2-tert-Butyl-4-fluoro-6-aminophenyl methyl carbonate

To a refluxing solution of 2-tert-butyl-4-fluoro-6-nitrophenyl methylcarbonate (250 mg, 0.92 mmol) and ammonium formate (250 mg, 4 mmol) inEtOH (10 mL) was added 5% Pd—C (170 mg). The mixture was refluxed foradditional 1 h, cooled and filtered through Celite. The solvent wasremoved by evaporation and the residue was purified by columnchromatography (0-15%, EtOAc—Hexane) to give2-tert-butyl-4-fluoro-6-aminophenyl methyl carbonate (C-6) (60 mg, 27%).HPLC ret. time 3.35 min, 10-99% CH₃CN, 5 min run; ESI-MS 242.0 m/z(MH⁺).

Example 6

Carbonic acid 2,4-di-tert-butyl-phenyl ester methyl ester

Methyl chloroformate (58 mL, 750 mmol) was added dropwise to a solutionof 2,4-di-tert-butyl-phenol (103.2 g, 500 mmol), Et₃N (139 mL, 1000mmol) and DMAP (3.05 g, 25 mmol) in dichloromethane (400 mL) cooled inan ice-water bath to 0° C. The mixture was allowed to warm to roomtemperature while stirring overnight, then filtered through silica gel(approx. 1 L) using 10% ethyl acetate-hexanes (˜4 L) as the eluent. Thecombined filtrates were concentrated to yield carbonic acid2,4-di-tert-butyl-phenyl ester methyl ester as a yellow oil (132 g,quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 7.35 (d, J=2.4 Hz, 1H), 7.29 (dd,J=8.5, 2.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 3.85 (s, 3H), 1.30 (s, 9H),1.29 (s, 9H).

Carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester andCarbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester

To a stirring mixture of carbonic acid 2,4-di-tert-butyl-phenyl estermethyl ester (4.76 g, 18 mmol) in conc. sulfuric acid (2 mL), cooled inan ice-water bath, was added a cooled mixture of sulfuric acid (2 mL)and nitric acid (2 mL). The addition was done slowly so that thereaction temperature did not exceed 50° C. The reaction was allowed tostir for 2 h while warming to room temperature. The reaction mixture wasthen added to ice-water and extracted into diethyl ether. The etherlayer was dried (MgSO₄), concentrated and purified by columnchromatography (0-10% ethyl acetate-hexanes) to yield a mixture ofcarbonic acid 2,4-di-tert-butyl-5-nitro-phenyl ester methyl ester andcarbonic acid 2,4-di-tert-butyl-6-nitro-phenyl ester methyl ester as apale yellow solid (4.28 g), which was used directly in the next step.

2,4-Di-tert-butyl-5-nitro-phenol and 2,4-Di-tert-butyl-6-nitro-phenol

The mixture of carbonic acid 2,4-di-tert-butyl-5-nitro-phenyl estermethyl ester and carbonic acid 2,4-di-tert-butyl-6-nitro-phenyl estermethyl ester (4.2 g, 12.9 mmol) was dissolved in MeOH (65 mL) and KOH(2.0 g, 36 mmol) was added. The mixture was stirred at room temperaturefor 2 h. The reaction mixture was then made acidic (pH 2-3) by addingconc. HCl and partitioned between water and diethyl ether. The etherlayer was dried (MgSO₄), concentrated and purified by columnchromatography (0-5% ethyl acetate-hexanes) to provide2,4-di-tert-butyl-5-nitro-phenol (1.31 g, 29% over 2 steps) and2,4-di-tert-butyl-6-nitro-phenol. 2,4-Di-tert-butyl-5-nitro-phenol: ¹HNMR (400 MHz, DMSO-d₆) δ 10.14 (s, 1H, OH), 7.34 (s, 1H), 6.83 (s, 1H),1.36 (s, 9H), 1.30 (s, 9H). 2,4-Di-tert-butyl-6-nitro-phenol: ¹H NMR(400 MHz, CDCl₃) δ 11.48 (s, 1H), 7.98 (d, J=2.5 Hz, 1H), 7.66 (d, J=2.4Hz, 1H), 1.47 (s, 9H), 1.34 (s, 9H).

C-9; 5-Amino-2,4-di-tert-butyl-phenol

To a reluxing solution of 2,4-di-tert-butyl-5-nitro-phenol (1.86 g, 7.4mmol) and ammonium formate (1.86 g) in ethanol (75 mL) was added Pd-5%wt. on activated carbon (900 mg). The reaction mixture was stirred atreflux for 2 h, cooled to room temperature and filtered through Celite.The Celite was washed with methanol and the combined filtrates wereconcentrated to yield 5-amino-2,4-di-tert-butyl-phenol as a grey solid(1.66 g, quant.). ¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H, OH), 6.84 (s,1H), 6.08 (s, 1H), 4.39 (s, 2H, NH₂), 1.27 (m, 18H); HPLC ret. time 2.72min, 10-99% CH₃CN, 5 min run; ESI-MS 222.4 m/z (MH⁺).

C-8; 6-Amino-2,4-di-tert-butyl-phenol

A solution of 2,4-di-tert-butyl-6-nitro-phenol (27 mg, 0.11 mmol) andSnCl₂.2H₂O (121 mg, 0.54 mmol) in EtOH (1.0 mL) was heated in microwaveoven at 100° C. for 30 min. The mixture was diluted with EtOAc andwater, basified with sat. NaHCO₃ and filtered through Celite. Theorganic layer was separated and dried over Na₂SO₄. Solvent was removedby evaporation to provide 6-amino-2,4-di-tert-butyl-phenol (C-8), whichwas used without further purification. HPLC ret. time 2.74 min, 10-99%CH₃CN, 5 min run; ESI-MS 222.5 m/z (MH⁺).

Example 7

4-tert-butyl-2-chloro-phenol

To a solution of 4-tert-butyl-phenol (40.0 g, 0.27 mol) and SO₂Cl₂ (37.5g, 0.28 mol) in CH₂Cl₂ was added MeOH (9.0 g, 0.28 mol) at 0° C. Afteraddition was complete, the mixture was stirred overnight at roomtemperature and then water (200 mL) was added. The resulting solutionwas extracted with ethyl acetate. The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated under vacuum. Theresidue was purified by column chromatography (Pet. Ether/EtOAc, 50:1)to give 4-tert-butyl-2-chloro-phenol (47.0 g, 95%).

4-tert-Butyl-2-chlorophenyl methyl carbonate

To a solution of 4-tert-butyl-2-chlorophenol (47.0 g, 0.25 mol) indichloromethane (200 mL) was added Et₃N (50.5 g, 0.50 mol), DMAP (1 g)and methyl chloroformate (35.4 g, 0.38 mol) at 0° C. The reaction wasallowed to warm to room temperature and stirred for additional 30 min.The reaction mixture was washed with H₂O and the organic layer was driedover Na₂SO₄ and concentrated to give 4-tert-butyl-2-chlorophenyl methylcarbonate (56.6 g, 92%), which was used directly in the next step.

4-tert-Butyl-2-chloro-5-nitrophenyl methyl carbonate

4-tert-Butyl-2-chlorophenyl methyl carbonate (36.0 g, 0.15 mol) wasdissolved in conc. H₂SO₄ (100 mL) at 0° C. KNO₃ (0.53 g, 5.2 mmol) wasadded in portions over 25 min. The reaction was stirred for 1.5 h andpoured into ice (200 g). The aqueous layer was extracted withdichloromethane. The combined organic layers were washed with aq.NaHCO₃, dried over Na₂SO₄ and concentrated under vacuum to give4-tert-butyl-2-chloro-5-nitrophenyl methyl carbonate (41.0 g), which wasused without further purification.

4-tert-Butyl-2-chloro-5-nitro-phenol

Potassium hydroxide (10.1 g, 181 mmol) was added to4-tert-butyl-2-chloro-5-nitrophenyl methyl carbonate (40.0 g, 139 mmol)in MeOH (100 mL). After 30 min, the reaction was acidified with 1N HCland extracted with dichloromethane. The combined organic layers werecombined, dried over Na₂SO₄ and concentrated under vacuum. The cruderesidue was purified by column chromatography (Pet. Ether/EtOAc, 30:1)to give 4-tert-butyl-2-chloro-5-nitro-phenol (23.0 g, 68% over 2 steps).

C-11; 4-tert-Butyl-2-chloro-5-amino-phenol

To a solution of 4-tert-butyl-2-chloro-5-nitro-phenol (12.6 g, 54.9mmol) in MeOH (50 mL) was added Ni (1.2 g). The reaction was shakenunder H₂ (1 atm) for 4 h. The reaction mixture was filtered and thefiltrate was concentrated. The residue was purified by columnchromatography (P.E./EtOAc, 20:1) to give4-tert-butyl-2-chloro-5-amino-phenol (C-11) (8.5 g, 78%). ¹H NMR(DMSO-d₆) δ 9.33 (s, 1H), 6.80 (s, 1H), 6.22 (s, 1H), 4.76 (s, 1H), 1.23(s, 9H); ESI-MS 200.1 m/z (MH⁺).

Example 8

2-Admantyl-4-methyl-phenyl ethyl carbonate

Ethyl chloroformate (0.64 mL, 6.7 mmol) was added dropwise to a solutionof 2-admantyl-4-methylphenol (1.09 g, 4.5 mmol), Et₃N (1.25 mL, 9 mmol)and DMAP (catalytic amount) in dichloromethane (8 mL) cooled in anice-water bath to 0° C. The mixture was allowed to warm to roomtemperature while stirring overnight, then filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (10-20%ethyl acetate-hexanes) to yield 2-admantyl-4-methyl-phenyl ethylcarbonate as a yellow oil (1.32 g, 94%).

2-Admantyl-4-methyl-5-nitrophenyl ethyl carbonate

To a cooled solution of 2-admantyl-4-methyl-phenyl ethyl carbonate (1.32g, 4.2 mmol) in H₂SO₄ (98%, 10 mL) was added KNO₃ (510 mg, 5.0 mmol) insmall portions at 0° C. The mixture was stirred for 3 h while warming toroom temperature, poured into ice and then extracted withdichloromethane. The combined organic layers were washed with NaHCO₃ andbrine, dried over MgSO₄ and concentrated to dryness. The residue waspurified by column chromatography (0-10% EtOAc-Hexane) to yield2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378 mg, 25%).

2-Admantyl-4-methyl-5-nitrophenol

To a solution of 2-admantyl-4-methyl-5-nitrophenyl ethyl carbonate (378mg, 1.05 mmol) in CH₂Cl₂ (5 mL) was added piperidine (1.0 mL). Thesolution was stirred at room temperature for 1 h, adsorbed onto silicagel under reduced pressure and purified by flash chromatography onsilica gel (0-15%, EtOAc-Hexanes) to provide2-admantyl-4-methyl-5-nitrophenol (231 mg, 77%).

C-12; 2-Admantyl-4-methyl-5-aminophenol

To a solution of 2-admantyl-4-methyl-5-nitrophenol (231 mg, 1.6 mmol) inEtOH (2 mL) was added Pd-5% wt on carbon (10 mg). The mixture wasstirred under H₂ (1 atm) overnight and then filtered through Celite. Thefiltrate was evaporated to dryness to provide2-admantyl-4-methyl-5-aminophenol (C-12), which was used without furtherpurification. HPLC ret. time 2.52 min, 10-99% CH₃CN, 5 min run; ESI-MS258.3 m/z (MH⁺).

Example 9

2-tert-Butyl-4-bromophenol

To a solution of 2-tert-butylphenol (250 g, 1.67 mol) in CH₃CN (1500 mL)was added NBS (300 g, 1.67 mol) at room temperature. After addition, themixture was stirred at room temperature overnight and then the solventwas removed. Petroleum ether (1000 mL) was added, and the resultingwhite precipitate was filtered off. The filtrate was concentrated underreduced pressure to give the crude 2-tert-butyl-4-bromophenol (380 g),which was used without further purification.

Methyl (2-tert-butyl-4-bromophenyl) carbonate

To a solution of 2-t-butyl-4-bromophenol (380 g, 1.67 mol) indichloromethane (1000 mL) was added Et₃N (202 g, 2 mol) at roomtemperature. Methyl chloroformate (155 mL) was added dropwise to theabove solution at 0° C. After addition, the mixture was stirred at 0° C.for 2 h., quenched with saturated ammonium chloride solution and dilutedwith water. The organic layer was separated and washed with water andbrine, dried over Na₂SO₄, and concentrated to provide the crude methyl(2-tert-butyl-4-bromophenyl) carbonate (470 g), which was used withoutfurther purification.

Methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate

Methyl (2-tert-butyl-4-bromophenyl) carbonate (470 g, 1.67 mol) wasdissolved in conc. H₂SO₄ (1000 ml) at 0° C. KNO₃ (253 g, 2.5 mol) wasadded in portions over 90 min. The reaction mixture was stirred at 0° C.for 2 h and poured into ice-water (20 L). The resulting precipitate wascollected via filtration and washed with water thoroughly, dried andrecrystallized from ether to give methyl(2-tert-butyl-4-bromo-5-nitrophenyl) carbonate (332 g, 60% over 3steps).

C-14-a; 2-tert-Butyl-4-bromo-5-nitro-phenol

To a solution of methyl (2-tert-butyl-4-bromo-5-nitrophenyl) carbonate(121.5 g, 0.366 mol) in methanol (1000 mL) was added potassium hydroxide(30.75 g, 0.549 mol) in portions. After addition, the mixture wasstirred at room temperature for 3 h and acidified with 1N HCl to pH 7.Methanol was removed and water was added. The mixture was extracted withethyl acetate and the organic layer was separated, dried over Na₂SO₄ andconcentrated to give 2-tert-butyl-4-bromo-5-nitro-phenol (C-14-a) (100g, 99%).

1-tert-Butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.1 g, 4mmol) and Cs₂CO₃ (1.56 g, 4.8 mmol) in DMF (8 mL) was added benzylbromide (500 μL, 4.2 mmol). The mixture was stirred at room temperaturefor 4 h, diluted with H₂O and extracted twice with EtOAc. The combinedorganic layers were washed with brine and dried over MgSO₄. Afterremoval of solvent, the residue was purified by column chloromatography(0-5% EtOAc-Hexane) to yield1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (1.37 g, 94%). ¹H NMR(400 MHz, CDCl₃) 7.62 (s, 1H), 7.53 (s, 1H), 7.43 (m, 5H), 5.22 (s, 2H),1.42 (s, 9H).

1-tert-Butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene

A mixture of 1-tert-butyl-2-(benzyloxy)-5-bromo-4-nitrobenzene (913 mg,2.5 mmol), KF (291 mg, 5 mmol), KBr (595 mg, 5 mmol), CuI (570 mg, 3mmol), methyl chlorodifluoroacetate (1.6 mL, 15 mmol) and DMF (5 mL) wasstirred at 125° C. in a sealed tube overnight, cooled to roomtemperature, diluted with water and extracted three times with EtOAc.The combined organic layers were washed with brine and dried overanhydrous MgSO₄. After removal of the solvent, the residue was purifiedby column chromatography (0-5% EtOAc-Hexane) to yield1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (591 mg,67%). ¹H NMR (400 MHz, CDCl₃) 7.66 (s, 1H), 7.37 (m, 5H), 7.19 (s, 1H),5.21 (s, 2H), 1.32 (s, 9H).

C-14; 5-Amino-2-tert-butyl-4-trifluoromethyl-phenol

To a refluxing solution of1-tert-butyl-2-(benzyloxy)-5-(trifluoromethyl)-4-nitrobenzene (353 mg,1.0 mmol) and ammonium formate (350 mg, 5.4 mmol) in EtOH (10 mL) wasadded 10% Pd—C (245 mg). The mixture was refluxed for additional 2 h,cooled to room temperature and filtered through Celite. After removal ofsolvent, the residue was purified by column chromatography to give5-Amino-2-tert-butyl-4-trifluoromethyl-phenol (C-14) (120 mg, 52%). ¹HNMR (400 MHz, CDCl₃) δ 7.21 (s, 1H), 6.05 (s, 1H), 1.28 (s, 9H); HPLCret. time 3.46 min, 10-99% CH₃CN, 5 min run; ESI-MS 234.1 m/z (MH⁺).

Example 10 General Scheme

Specific Example

2-tert-Butyl-4-(2-ethoxyphenyl)-5-nitrophenol

To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (8.22 g, 30mmol) in DMF (90 mL) was added 2-ethoxyphenyl boronic acid (5.48 g, 33mmol), potassium carbonate (4.56 g, 33 mmol), water (10 ml) andPd(PPh₃)₄ (1.73 g, 1.5 mmol). The mixture was heated at 90° C. for 3 hunder nitrogen. The solvent was removed under reduced pressure. Theresidue was partitioned between water and ethyl acetate. The combinedorganic layers were washed with water and brine, dried and purified bycolumn chromatography (petroleum ether-ethyl acetate, 10:1) to afford2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (9.2 g, 92%). ¹H NMR(DMSO-d₆) δ 10.38 (s, 1H), 7.36 (s, 1H), 7.28 (m, 2H), 7.08 (s, 1H),6.99 (t, 1H, J=7.35 Hz), 6.92 (d, 1H, J=8.1 Hz), 3.84 (q, 2H, J=6.6 Hz),1.35 (s, 9H), 1.09 (t, 3H, J=6.6 Hz); ESI-MS 314.3 m/z (MH⁺).

C-15; 2-tert-Butyl-4-(2-ethoxyphenyl)-5-aminophenol

To a solution of 2-tert-butyl-4-(2-ethoxyphenyl)-5-nitrophenol (3.0 g,9.5 mmol) in methanol (30 ml) was added Raney Ni (300 mg). The mixturewas stirred under H₂ (1 atm) at room temperature for 2 h. The catalystwas filtered off and the filtrate was concentrated. The residue waspurified by column chromatography (petroleum ether-ethyl acetate, 6:1)to afford 2-tert-butyl-4-(2-ethoxyphenyl)-5-aminophenol (C-15) (2.35 g,92%). ¹H NMR (DMSO-d₆) δ 8.89 (s, 1H), 7.19 (t, 1H, J=4.2 Hz), 7.10 (d,1H, J=1.8 Hz), 7.08 (d, 1H, J=1.8 Hz), 6.94 (t, 1H, J=3.6 Hz), 6.67 (s,1H), 6.16 (s, 1H), 4.25 (s, 1H), 4.00 (q, 2H, J=6.9 Hz), 1.26 (s, 9H),1.21 (t, 3H, J=6.9 Hz); ESI-MS 286.0 m/z (MH⁺).

Other Examples

C-16; 2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol

2-tert-Butyl-4-(3-ethoxyphenyl)-5-aminophenol (C-16) was synthesizedfollowing the general scheme above starting from2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and 3-ethoxyphenyl boronicacid. HPLC ret. time 2.77 min, 10-99% CH₃CN, 5 min run; ESI-MS 286.1 m/z(MH⁺).

C-17; 2-tert-Butyl-4-(3-methoxycarbonylphenyl)-5-aminophenol (C-17)

2-tert-Butyl-4-(3-methoxycarbonylphenyl)-5-aminophenol (C-17) wassynthesized following the general scheme above starting from2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) and3-(methoxycarbonyl)phenylboronic acid. HPLC ret. time 2.70 min, 10-99%CH₃CN, 5 min run; ESI-MS 300.5 m/z (MH⁺).

Example 11

1-tert-Butyl-2-methoxy-5-bromo-4-nitrobenzene

To a mixture of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (1.5 g, 5.5mmol) and Cs₂CO₃ (2.2 g, 6.6 mmol) in DMF (6 mL) was added methyl iodide(5150 μL, 8.3 mmol). The mixture was stirred at room temperature for 4h, diluted with H₂O and extracted twice with EtOAc. The combined organiclayers were washed with brine and dried over MgSO₄. After removal ofsolvent, the residue was washed with hexane to yield1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (1.1 g, 69%). ¹H NMR (400MHz, CDCl₃) δ 7.58 (s, 1H), 7.44 (s, 1H), 3.92 (s, 3H), 1.39 (s, 9H).

1-tert-Butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene

A mixture of 1-tert-butyl-2-methoxy-5-bromo-4-nitrobenzene (867 mg, 3.0mmol), KF (348 mg, 6 mmol), KBr (714 mg, 6 mmol), CuI (684 mg, 3.6mmol), methyl chlorodifluoroacetate (2.2 mL, 21.0 mmol) in DMF (5 mL)was stirred at 125° C. in a sealed tube overnight, cooled to roomtemperature, diluted with water and extracted three times with EtOAc.The combined organic layers were washed with brine and dried overanhydrous MgSO₄. After removal of the solvent, the residue was purifiedby column chromatography (0-5% EtOAc-Hexane) to yield1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (512 mg, 61%).¹H NMR (400 MHz, CDCl₃) δ 7.60 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 1.33(s, 9H).

C-18; 1-tert-Butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzene

To a refluxing solution of1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-nitrobenzene (473 mg, 1.7mmol) and ammonium formate (473 mg, 7.3 mmol) in EtOH (10 mL) was added10% Pd—C (200 mg). The mixture was refluxed for 1 h, cooled and filteredthrough Celite. The solvent was removed by evaporation to give1-tert-butyl-2-methoxy-5-(trifluoromethyl)-4-aminobenzene (C-18) (403mg, 95%). ¹H NMR (400 MHz, CDCl₃) δ 7.19 (s, 1H), 6.14 (s, 1H), 4.02(bs, 2H), 3.74 (s, 3H), 1.24 (s, 9H).

Example 12

C-27; 2-tert-Butyl-4-bromo-5-amino-phenol

To a solution of 2-tert-butyl-4-bromo-5-nitrophenol (C-14-a) (12 g, 43.8mmol) in MeOH (90 mL) was added Ni (2.4 g). The reaction mixture wasstirred under H₂ (1 atm) for 4 h. The mixture was filtered and thefiltrate was concentrated. The crude product was recrystallized fromethyl acetate and petroleum ether to give2-tert-butyl-4-bromo-5-amino-phenol (C-27) (7.2 g, 70%). ¹H NMR(DMSO-d₆) δ 9.15 (s, 1H), 6.91 (s, 1H), 6.24 (s, 1H), 4.90 (br s, 2H),1.22 (s, 9H); ESI-MS 244.0 m/z (MH⁺).

Example 13

C-24; 2,4-Di-tert-butyl-6-(N-methylamino)phenol

A mixture of 2,4-di-tert-butyl-6-amino-phenol (C-9) (5.08 g, 23 mmol),NaBH₃CN (4.41 g, 70 mmol) and paraformaldehyde (2.1 g, 70 mmol) inmethanol (50 mL) was stirred at reflux for 3 h. After removal of thesolvent, the residue was purified by column chromatography (petroleumether-EtOAc, 30:1) to give 2,4-di-tert-butyl-6-(N-methylamino)phenol(C-24) (800 mg, 15%). ¹H NMR (DMSO-d₆) δ 8.67 (s, 1H), 6.84 (s, 1H),5.99 (s, 1H), 4.36 (q, J=4.8 Hz, 1H), 2.65 (d, J=4.8 Hz, 3H), 1.23 (s,18H); ESI-MS 236.2 m/z (MH⁺).

Example 14

2-Methyl-2-phenyl-propan-1-ol

To a solution of 2-methyl-2-phenyl-propionic acid (82 g, 0.5 mol) in THF(200 mL) was added dropwise borane-dimethyl sulfide (2M, 100 mL) at 0-5°C. The mixture was stirred at this temperature for 30 min and thenheated at reflux for 1 h. After cooling, methanol (150 mL) and water (50mL) were added. The mixture was extracted with EtOAc (100 mL×3), and thecombined organic layers were washed with water and brine, dried overNa₂SO₄ and concentrated to give 2-methyl-2-phenyl-propan-1-ol as an oil(70 g, 77%).

2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene

To a suspension of NaH (29 g, 0.75 mol) in THF (200 mL) was addeddropwise a solution of 2-methyl-2-phenyl-propan-1-ol (75 g, 0.5 mol) inTHF (50 mL) at 0° C. The mixture was stirred at 20° C. for 30 min andthen a solution of 1-bromo-2-methoxy-ethane (104 g, 0.75 mol) in THF(100 mL) was added dropwise at 0° C. The mixture was stirred at 20° C.overnight, poured into water (200 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with water and brine,dried over Na₂SO₄, and concentrated. The residue was purified by columnchromatography (silica gel, petroleum ether) to give2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene as an oil (28 g, 27%).

1-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene

To a solution of 2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-benzene (52 g,0.25 mol) in CHCl₃ (200 mL) was added KNO₃ (50.5 g, 0.5 mol) and TMSCl(54 g, 0.5 mol). The mixture was stirred at 20° C. for 30 min and thenAlCl₃ (95 g, 0.7 mol) was added. The reaction mixture was stirred at 20°C. for 1 h and poured into ice-water. The organic layer was separatedand the aqueous layer was extracted with CHCl₃ (50 mL×3). The combinedorganic layers were washed with water and brine, dried over Na₂SO₄, andconcentrated. The residue was purified by column chromatography (silicagel, petroleum ether) to obtain1-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene (6 g, 10%).

4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine

A suspension of1-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-4-nitro-benzene (8.1 g, 32mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H₂ (1 atm) atroom temperature for 1 h. The catalyst was filtered off and the filtratewas concentrated to obtain4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine (5.5 g, 77%).

4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine

To a solution of 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenylamine(5.8 g, 26 mmol) in H₂SO₄ (20 mL) was added KNO₃ (2.63 g, 26 mmol) at 0°C. After addition was complete, the mixture was stirred at thistemperature for 20 min and then poured into ice-water. The mixture wasextracted with EtOAc (50 mL×3). The combined organic layers were washedwith water and brine, dried over Na₂SO₄, and concentrated. The residuewas purified by column chromatography (petroleum ether-EtOAc, 100:1) togive 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5g, 71%).

N-{4-[2-(2-Methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide

To a suspension of NaHCO₃ (10 g, 0.1 mol) in dichloromethane (50 mL) wasadded 4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenylamine (5g, 30 mmol) and acetyl chloride (3 mL, 20 mmol) at 0-5° C. The mixturewas stirred overnight at 15° C. and then poured into water (200 mL). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (50 mL×2). The combined organic layers were washed withwater and brine, dried over Na₂SO₄, and concentrated to dryness to giveN-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide(5.0 g, 87%).

N-{3-Amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide

A mixture ofN-{4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-3-nitro-phenyl}-acetamide(5 g, 16 mmol) and Raney Ni (1 g) in MeOH (50 mL) was stirred under H₂(1 atm) at room temperature 1 h. The catalyst was filtered off and thefiltrate was concentrated. The residue was purified by columnchromatography (petroleum ether-EtOAc, 100:1) to giveN-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide(1.6 g, 35%).

N-{3-Hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide

To a solution ofN-{3-amino-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide(1.6 g, 5.7 mmol) in H₂SO₄ (15%, 6 mL) was added NaNO₂ at 0-5° C. Themixture was stirred at this temperature for 20 min and then poured intoice water. The mixture was extracted with EtOAc (30 mL×3). The combinedorganic layers were washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography(petroleum ether-EtOAc, 100:1) to giveN-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide(0.7 g, 38%).

C-25; 2-(1-(2-Methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol

A mixture ofN-{3-hydroxy-4-[2-(2-methoxy-ethoxy)-1,1-dimethyl-ethyl]-phenyl}-acetamide(1 g, 3.5 mmol) and HCl (5 mL) was heated at reflux for 1 h. The mixturewas basified with Na₂CO₃ solution to pH 9 and then extracted with EtOAc(20 mL×3). The combined organic layers were washed with water and brine,dried over Na₂SO₄ and concentrated to dryness. The residue was purifiedby column chromatography (petroleum ether-EtOAc, 100:1) to obtain2-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)-5-aminophenol (C-25) (61 mg,6%). ¹H NMR (CDCl₃) δ 9.11 (br s, 1H), 6.96-6.98 (d, J=8 Hz, 1H),6.26-6.27 (d, J=4 Hz, 1H), 6.17-6.19 (m, 1H), 3.68-3.69 (m, 2H),3.56-3.59 (m, 4H), 3.39 (s, 3H), 1.37 (s, 6H); ESI-MS 239.9 m/z (MH⁺).

Example 15

4,6-di-tert-Butyl-3-nitrocyclohexa-3,5-diene-1,2-dione

To a solution of 3,5-di-tert-butylcyclohexa-3,5-diene-1,2-dione (4.20 g,19.1 mmol) in acetic acid (115 mL) was slowly added HNO₃ (15 mL). Themixture was heated at 60° C. for 40 min before it was poured into H₂O(50 mL). The mixture was allowed to stand at room temperature for 2 h,then was placed in an ice bath for 1 h. The solid was collected andwashed with water to provide4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (1.2 g, 24%). ¹HNMR (400 MHz, DMSO-d₆) δ 6.89 (s, 1H), 1.27 (s, 9H), 1.24 (s, 9H).

4,6-Di-tert-butyl-3-nitrobenzene-1,2-diol

In a separatory funnel was placed THF/H₂O (1:1, 400 mL),4,6-di-tert-butyl-3-nitrocyclohexa-3,5-diene-1,2-dione (4.59 g, 17.3mmol) and Na₂S₂O₄ (3 g, 17.3 mmol). The separatory funnel was stopperedand was shaken for 2 min. The mixture was diluted with EtOAc (20 mL).The layers were separated and the organic layer was washed with brine,dried over MgSO₄ and concentrated to provide4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (3.4 g, 74%), which was usedwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H),8.76 (s, 1H), 6.87 (s, 1H), 1.35 (s, 9H), 1.25 (s, 9H).

C-26; 4,6-Di-tert-butyl-3-aminobenzene-1,2-diol

To a solution of 4,6-di-tert-butyl-3-nitrobenzene-1,2-diol (1.92 g, 7.2mmol) in EtOH (70 mL) was added Pd-5% wt. on carbon (200 mg). Themixture was stirred under H₂ (1 atm) for 2 h. The reaction was rechargedwith Pd-5% wt. on carbon (200 mg) and stirred under H₂ (1 atm) foranother 2 h. The mixture was filtered through Celite and the filtratewas concentrated and purified by column chromatography (10-40% ethylacetate-hexanes) to give 4,6-di-tert-butyl-3-aminobenzene-1,2-diol(C-26) (560 mg, 33%). ¹H NMR (400 MHz, CDCl₃) δ 7.28 (s, 1H), 1.42 (s,9H), 1.38 (s, 9H).

Anilines

Example 1 General Scheme

Specific Example

D-1; 4-Chloro-benzene-1,3-diamine

A mixture of 1-chloro-2,4-dinitro-benzene (100 mg, 0.5 mmol) andSnCl₂.2H₂O (1.12 g, 5 mmol) in ethanol (2.5 mL) was stirred at roomtemperature overnight. Water was added and then the mixture was basifiedto pH 7-8 with saturated NaHCO₃ solution. The solution was extractedwith ethyl acetate. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and concentrated to yield4-chloro-benzene-1,3-diamine (D-1) (79 mg, quant.). HPLC ret. time 0.38min, 10-99% CH₃CN, 5 min run; ESI-MS 143.1 m/z (MH⁺)

Other Examples

D-2; 4,6-Dichloro-benzene-1,3-diamine

4,6-Dichloro-benzene-1,3-diamine (D-2) was synthesized following thegeneral scheme above starting from 1,5-dichloro-2,4-dinitro-benzene.Yield (95%). HPLC ret. time 1.88 min, 10-99% CH₃CN, 5 min run; ESI-MS177.1 m/z (MH⁺).

D-3; 4-Methoxy-benzene-1,3-diamine

4-Methoxy-benzene-1,3-diamine (D-3) was synthesized following thegeneral scheme above starting from 1-methoxy-2,4-dinitro-benzene. Yield(quant.). HPLC ret. time 0.31 min, 10-99% CH₃CN, 5 min run.

D-4; 4-Trifluoromethoxy-benzene-1,3-diamine

4-Trifluoromethoxy-benzene-1,3-diamine (D-4) was synthesized followingthe general scheme above starting from2,4-dinitro-1-trifluoromethoxy-benzene. Yield (89%). HPLC ret. time 0.91min, 10-99% CH₃CN, 5 min run; ESI-MS 193.3 m/z (MH⁺).

D-5; 4-Propoxybenzene-1,3-diamine

4-Propoxybenzene-1,3-diamine (D-5) was synthesized following the generalscheme above starting from 5-nitro-2-propoxy-phenylamine. Yield (79%).HPLC ret. time 0.54 min, 10-99% CH₃CN, 5 min run; ESI-MS 167.5 m/z(MH⁺).

Example 2 General Scheme

Specific Example

2,4-Dinitro-propylbenzene

A solution of propylbenzene (10 g, 83 mmol) in conc. H₂SO₄ (50 mL) wascooled at 0° C. for 30 min, and a solution of conc. H₂SO₄ (50 mL) andfuming HNO₃ (25 mL), previously cooled to 0° C., was added in portionsover 15 min. The mixture was stirred at 0° C. for additional 30 min, andthen allowed to warm to room temperature. The mixture was poured intoice (200 g)-water (100 mL) and extracted with ether (2×100 mL). Thecombined extracts were washed with H₂O (100 mL) and brine (100 mL),dried over MgSO₄, filtered and concentrated to afford2,4-dinitro-propylbenzene (15.6 g, 89%). ¹H NMR (CDCl₃, 300 MHz) δ 8.73(d, J=2.2 Hz, 1H), 8.38 (dd, J=8.3, J=2.2, 1H), 7.6 (d, J=8.5 Hz, 1H),2.96 (dd, 2H), 1.73 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

D-6; 4-Propyl-benzene-1,3-diamine

To a solution of 2,4-dinitro-propylbenzene (2.02 g, 9.6 mmol) in ethanol(100 mL) was added SnCl₂ (9.9 g, 52 mmol) followed by conc. HCl (10 mL).The mixture was refluxed for 2 h, poured into ice-water (100 mL), andneutralized with solid sodium bicarbonate. The solution was furtherbasified with 10% NaOH solution to pH 10 and extracted with ether (2×100mL). The combined organic layers were washed with brine (100 mL), driedover MgSO₄, filtered, and concentrated to provide4-propyl-benzene-1,3-diamine (D-6) (1.2 g, 83%). No further purificationwas necessary for use in the next step; however, the product was notstable for an extended period of time. ¹H NMR (CDCl₃, 300 MHz) δ 6.82(d, J=7.9 Hz, 1H), 6.11 (dd, J=7.5, J=2.2 Hz, 1H), 6.06 (d, J=2.2 Hz,1H), 3.49 (br s, 4H, NH₂), 2.38 (t, J=7.4 Hz, 2H), 1.58 (m, 2H), 0.98(t, J=7.2 Hz, 3H); ESI-MS 151.5 m/z (MH⁺).

Other Examples

D-7; 4-Ethylbenzene-1,3-diamine

4-Ethylbenzene-1,3-diamine (D-7) was synthesized following the generalscheme above starting from ethylbenezene. Overall yield (76%).

D-8; 4-Isopropylbenzene-1,3-diamine

4-Isopropylbenzene-1,3-diamine (D-8) was synthesized following thegeneral scheme above starting from isopropylbenezene. Overall yield(78%).

D-9; 4-tert-Butylbenzene-1,3-diamine

4-tert-Butylbenzene-1,3-diamine (D-9) was synthesized following thegeneral scheme above starting from tert-butylbenzene. Overall yield(48%). ¹H NMR (400 MHz, CDCl₃) δ 7.01 (d, J=8.3 Hz, 1H), 6.10 (dd,J=2.4, 8.3 Hz, 1H), 6.01 (d, J=2.4 Hz, 1H), 3.59 (br, 4H), 1.37 (s, 9H);¹³C NMR (100 MHz, CDCl₃) δ 145.5, 145.3, 127.6, 124.9, 105.9, 104.5,33.6, 30.1; ESI-MS 164.9 m/z (MH⁺).

Example 3 General Scheme

Specific Example

4-tert-Butyl-3-nitro-phenylamine

To a mixture of 4-tert-butyl-phenylamine (10.0 g, 67.01 mmol) dissolvedin H₂SO₄ (98%, 60 mL) was slowly added KNO₃ (8.1 g, 80.41 mmol) at 0° C.After addition, the reaction was allowed to warm to room temperature andstirred overnight. The mixture was then poured into ice-water andbasified with sat. NaHCO₃ solution to pH 8. The mixture was extractedseveral times with CH₂Cl₂. The combined organic layers were washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography (petroleum ether-EtOAc, 10:1) to give4-tert-butyl-3-nitro-phenylamine (10 g, 77%).

(4-tert-Butyl-3-nitro-phenyl)-carbamic acid tert-butyl ester

A mixture of 4-tert-butyl-3-nitro-phenylamine (4.0 g, 20.6 mmol) andBoc₂O (4.72 g, 21.6 mmol) in NaOH (2N, 20 mL) and THF (20 mL) wasstirred at room temperature overnight. THF was removed under reducedpressure. The residue was dissolved in water and extracted with CH₂Cl₂.The organic layer was washed with NaHCO₃ and brine, dried over Na₂SO₄and concentrated to afford (4-tert-butyl-3-nitro-phenyl)-carbamic acidtert-butyl ester (4.5 g, 74%).

D-10; (3-Amino-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester

A suspension of (4-tert-butyl-3-nitro-phenyl)-carbamic acid tert-butylester (3.0 g, 10.19 mol) and 10% Pd—C (1 g) in MeOH (40 mL) was stirredunder H₂ (1 atm) at room temperature overnight. After filtration, thefiltrate was concentrated and the residue was purified by columnchromatograph (petroleum ether-EtOAc, 5:1) to give(3-amino-4-tert-butyl-phenyl)-carbamic acid tert-butyl ester (D-10) as abrown oil (2.5 g, 93%). ¹H NMR (CDCl₃) δ 7.10 (d, J=8.4 Hz, 1H), 6.92(s, 1H), 6.50-6.53 (m, 1H), 6.36 (s, 1H), 3.62 (br s, 2H), 1.50 (s, 9H),1.38 (s, 9H); ESI-MS 528.9 m/z (2M+H⁺).

Other Examples

D-11; (3-Amino-4-isopropyl-phenyl)-carbamic acid tert-butyl ester

(3-Amino-4-isopropyl-phenyl)-carbamic acid tert-butyl ester (D-11) wassynthesized following the general scheme above starting fromisopropylbenezene. Overall yield (56%).

D-12; (3-Amino-4-ethyl-phenyl)-carbamic acid tert-butyl ester

(3-Amino-4-ethyl-phenyl)-carbamic acid tert-butyl ester (D-12) wassynthesized following the general scheme above starting fromethylbenezene. Overall yield (64%). ¹H NMR (CD₃OD, 300 MHz) δ 6.87 (d,J=8.0 Hz, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.63 (dd, J=8.1, J=2.2, 1H), 2.47(q, J=7.4 Hz, 2H), 1.50 (s, 9H), 1.19 (t, J=7.4 Hz, 3H); ESI-MS 237.1m/z (MH⁺).

D-13; (3-Amino-4-propyl-phenyl)-carbamic acid tert-butyl ester

(3-Amino-4-propyl-phenyl)-carbamic acid tert-butyl ester (D-13) wassynthesized following the general scheme above starting frompropylbenezene. Overall yield (48%).

Example 4

(3-Amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester

A solution of 4-tert-butylbenzene-1,3-diamine (D-9) (657 mg, 4 mmol) andpyridine (0.39 mL, 4.8 mmol) in CH₂Cl₂/MeOH (12/1, 8 mL) was cooled to0° C., and a solution of benzyl chloroformate (0.51 mL, 3.6 mmol) inCH₂Cl₂ (8 mL) was added dropwise over 10 min. The mixture was stirred at0° C. for 15 min, then warmed to room temperature. After 1 h, themixture was washed with 1M citric acid (2×20 mL), saturated aqueoussodium bicarbonate (20 mL), dried (Na₂SO₄), filtered and concentrated invacuo to afford the crude (3-amino-4-tert-butyl-phenyl)-carbamic acidbenzyl ester as a brown viscous gum (0.97 g), which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.41-7.32 (m, 6H), 7.12(d, J=8.5 Hz, 1H), 6.89 (br s, 1H), 6.57 (dd, J=2.3, 8.5 Hz, 1H), 5.17(s, 2H), 3.85 (br s, 2H), 1.38 (s, 9H); ¹³C NMR (100 MHz, CDCl₃,rotameric) δ 153.3 (br), 145.3, 136.56, 136.18, 129.2, 128.73, 128.59,128.29, 128.25, 127.14, 108.63 (br), 107.61 (br), 66.86, 33.9, 29.7;ESI-MS 299.1 m/z (MH⁺).

(4-tert-Butyl-3-formylamino-phenyl)-carbamic acid benzyl ester

A solution of (3-amino-4-tert-butyl-phenyl)-carbamic acid benzyl ester(0.97 g, 3.25 mmol) and pyridine (0.43 mL, 5.25 mmol) in CH₂Cl₂ (7.5 mL)was cooled to 0° C., and a solution of formic-acetic anhydride (3.5mmol, prepared by mixing formic acid (158 μL, 4.2 mmol, 1.3 equiv) andacetic anhydride (0.32 mL, 3.5 mmol, 1.1 eq.) neat and ageing for 1hour) in CH₂Cl₂ (2.5 mL) was added dropwise over 2 min. After theaddition was complete, the mixture was allowed to warm to roomtemperature, whereupon it deposited a precipitate, and the resultingslurry was stirred overnight. The mixture was washed with 1 M citricacid (2×20 mL), saturated aqueous sodium bicarbonate (20 mL), dried(Na₂SO₄), and filtered. The cloudy mixture deposited a thin bed of solidabove the drying agent, HPLC analysis showed this to be the desiredformamide. The filtrate was concentrated to approximately 5 mL, anddiluted with hexane (15 mL) to precipitate further formamide. The dryingagent (Na₂SO₄) was slurried with methanol (50 mL), filtered, and thefiltrate combined with material from the CH₂Cl₂/hexanerecrystallisation. The resultant mixture was concentrated to afford(4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester as anoff-white solid (650 mg, 50% over 2 steps). ¹H and ¹³C NMR (CD₃OD) showthe product as a rotameric mixture. ¹H NMR (400 MHz, CD₃OD, rotameric) δ8.27 (s, 1H-a), 8.17 (s, 1H-b), 7.42-7.26 (m, 8H), 5.17 (s, 1H-a), 5.15(s, 1H-b), 4.86 (s, 2H), 1.37 (s, 9H-a), 1.36 (s, 9H-b); ¹³C NMR (100MHz, CD₃OD, rotameric) δ 1636.9, 163.5, 155.8, 141.40, 141.32, 139.37,138.88, 138.22, 138.14, 136.4, 135.3, 129.68, 129.65, 129.31, 129.24,129.19, 129.13, 128.94, 128.50, 121.4 (br), 118.7 (br), 67.80, 67.67,35.78, 35.52, 31.65, 31.34; ESI-MS 327.5 m/z (MH⁺).

N-(5-Amino-2-tert-butyl-phenyl)-formamide

A 100 mL flask was charged with(4-tert-butyl-3-formylamino-phenyl)-carbamic acid benzyl ester (650 mg,1.99 mmol), methanol (30 mL) and 10% Pd—C (50 mg), and stirred under H₂(1 atm) for 20 h. CH₂Cl₂ (5 mL) was added to quench the catalyst, andthe mixture then filtered through Celite, and concentrated to affordN-(5-amino-2-tert-butyl-phenyl)-formamide as an off-white solid (366 mg,96%). Rotameric by ¹H and ¹³C NMR (DMSO-d₆). ¹H NMR (400 MHz, DMSO-d₆,rotameric) δ 9.24 (d, J=10.4 Hz, 1H), 9.15 (s, 1H), 8.23 (d, J=1.5 Hz,1H), 8.06 (d, J=10.4 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 7.02 (d, J=8.5 Hz,1H), 6.51 (d, J=2.5 Hz, 1H), 6.46 (dd, J=2.5, 8.5 Hz, 1H), 6.39 (dd,J=2.5, 8.5 Hz, 1H), 6.29 (d, J=2.5 Hz, 1H), 5.05 (s, 2H), 4.93 (s, 2H),1.27 (s, 9H); ¹³C NMR (100 MHz, DMSO-d₆, rotameric) δ 164.0, 160.4,147.37, 146.74, 135.38, 135.72, 132.48, 131.59, 127.31, 126.69, 115.15,115.01, 112.43, 112.00, 33.92, 33.57, 31.33, 30.92; ESI-MS 193.1 m/z(MH⁺).

D-14; 4-tert-butyl-N³-methyl-benzene-1,3-diamine

A 100 mL flask was charged withN-(5-amino-2-tert-butyl-phenyl)-formamide (340 mg, 1.77 mmol) and purgedwith nitrogen. THF (10 mL) was added, and the solution was cooled to 0°C. A solution of lithium aluminum hydride in THF (4.4 mL, 1M solution)was added over 2 min. The mixture was then allowed to warm to roomtemperature. After refluxing for 15 h, the yellow suspension was cooledto 0° C., quenched with water (170 μL), 15% aqueous NaOH (170 μL), andwater (510 μL) which were added sequentially and stirred at roomtemperature for 30 min. The mixture was filtered through Celite, and thefilter cake washed with methanol (50 mL). The combined filtrates wereconcentrated in vacuo to give a gray-brown solid, which was partitionedbetween chloroform (75 mL) and water (50 mL). The organic layer wasseparated, washed with water (50 mL), dried (Na₂SO₄), filtered, andconcentrated to afford 4-tert-butyl-N³-methyl-benzene-1,3-diamine (D-14)as a brown oil which solidified on standing (313 mg, 98%). ¹H NMR (400MHz, CDCl₃) δ 7.01 (d, J=8.1 Hz, 1H), 6.05 (dd, J=2.4, 8.1 Hz, 1H), 6.03(d, J=2.4 Hz, 1H), 3.91 (br s, 1H), 3.52 (br s, 2H), 2.86 (s, 3H), 1.36(s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 148.4, 145.7, 127.0, 124.3, 103.6,98.9, 33.5, 31.15, 30.31; ESI-MS 179.1 m/z (MH⁺).

Example 5 General Scheme

Specific Example

2,4-Dinitro-propylbenzene

A solution of propylbenzene (10 g, 83 mmol) in conc. H₂SO₄ (50 mL) wascooled at 0° C. for 30 mins, and a solution of conc. H₂SO₄ (50 mL) andfuming HNO₃ (25 mL), previously cooled to 0° C., was added in portionsover 15 min. The mixture was stirred at 0° C. for additional 30 min. andthen allowed to warm to room temperature. The mixture was poured intoice (200 g)-water (100 mL) and extracted with ether (2×100 mL). Thecombined extracts were washed with H₂O (100 mL) and brine (100 mL),dried over MgSO₄, filtered and concentrated to afford2,4-dinitro-propylbenzene (15.6 g, 89%). ¹H NMR (CDCl₃, 300 MHz) δ 8.73(d, J=2.2 Hz, 1H), 8.38 (dd, J=8.3, 2.2 Hz, 1H), 7.6 (d, J=8.5 Hz, 1H),2.96 (m, 2H), 1.73 (m, 2H), 1.06 (t, J=7.4 Hz, 3H).

4-Propyl-3-nitroaniline

A suspension of 2,4-dinitro-propylbenzene (2 g, 9.5 mmol) in H₂O (100mL) was heated near reflux and stirred vigorously. A clear orange-redsolution of polysulfide (300 mL (10 eq.), previously prepared by heatingsodium sulfide nanohydrate (10.0 g), sulfur powder (2.60 g) and H₂O (400mL), was added dropwise over 45 mins. The red-brown solution was heatedat reflux for 1.5 h. The mixture was cooled to 0° C. and then extractedwith ether (2×200 mL). The combined organic extracts were dried overMgSO₄, filtered, and concentrated under reduced pressure to afford4-propyl-3-nitroaniline (1.6 g, 93%), which was used without furtherpurification.

(3-Nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester

4-Propyl-3-nitroaniline (1.69 g, 9.4 mmol) was dissolved in pyridine (30mL) with stirring. Boc anhydride (2.05 g, 9.4 mmol) was added. Themixture was stirred and heated at reflux for 1 h before the solvent wasremoved in vacuo. The oil obtained was re-dissolved in CH₂Cl₂ (300 mL)and washed with water (300 mL) and brine (300 mL), dried over Na₂SO₄,filtered, and concentrated. The crude oil that contained both mono- andbis-acylated nitro products was purified by column chromatography (0-10%CH₂Cl₂-MeOH) to afford (3-nitro-4-propyl-phenyl)-carbamic acidtert-butyl ester (2.3 g, 87%).

Methyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester

To a solution of (3-nitro-4-propyl-phenyl)-carbamic acid tert-butylester (200 mg, 0.71 mmol) in DMF (5 mL) was added Ag₂O (110 g, 6.0 mmol)followed by methyl iodide (0.20 mL, 3.2 mmol). The resulting suspensionwas stirred at room temperature for 18 h and filtered through a pad ofCelite. The filter cake was washed with CH₂Cl₂ (10 mL). The filtrate wasconcentrated in vacuo. The crude oil was purified by columnchromatography (0-10% CH₂Cl₂-MeOH) to affordmethyl-(3-nitro-4-propyl-phenyl)-carbamic acid tert-butyl ester as ayellow oil (110 mg, 52%). ¹H NMR (CDCl₃, 300 MHz) δ 7.78 (d, J=2.2 Hz,1H), 7.42 (dd, J=8.2, 2.2 Hz, 1H), 7.26 (d, J=8.2 Hz, 1H), 3.27 (s, 3H),2.81 (t, J=7.7 Hz, 2H), 1.66 (m, 2H), 1.61 (s, 9H), 0.97 (t, J=7.4 Hz,3H).

D-15; (3-Amino-4-propyl-phenyl)-methyl-carbamic acid tert-butyl ester

To a solution of methyl-(3-nitro-4-propyl-phenyl)-carbamic acidtert-butyl ester (110 mg, 0.37 mmol) in EtOAc (10 ml) was added 10% Pd—C(100 mg). The resulting suspension was stirred at room temperature underH₂ (1 atm) for 2 days. The progress of the reaction was monitored byTLC. Upon completion, the reaction mixture was filtered through a pad ofCelite. The filtrate was concentrated in vacuo to afford(3-Amino-4-propyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-15)as a colorless crystalline compound (80 mg, 81%). ESI-MS 265.3 m/z(MH⁺).

Other Examples

D-16; (3-Amino-4-ethyl-phenyl)-methyl-carbamic acid tert-butyl ester

(3-Amino-4-ethyl-phenyl)-methyl-carbamic acid tert-butyl ester (D-16)was synthesized following the general scheme above starting fromethylbenezene. Overall yield (57%).

D-17; (3-Amino-4-isopropyl-phenyl)-methyl-carbamic acid tert-butyl ester

(3-Amino-4-isopropyl-phenyl)-methyl-carbamic acid tert-butyl ester(D-17) was synthesized following the general scheme above starting fromisopropylbenezene. Overall yield (38%).

Example 6

2′-Ethoxy-2,4-dinitro-biphenyl

A pressure flask was charged with 2-ethoxyphenylboronic acid (0.66 g,4.0 mmol), KF (0.77 g, 13 mmol), Pd₂(dba)₃ (16 mg, 0.02 mmol), and2,4-dinitro-bromobenzene (0.99 g, 4.0 mmol) in THF (5 mL). The vesselwas purged with argon for 1 min followed by the addition oftri-tert-butylphosphine (0.15 ml, 0.48 mmol, 10% solution in hexanes).The reaction vessel was purged with argon for additional 1 min., sealedand heated at 80° C. overnight. After cooling to room temperature, thesolution was filtered through a plug of Celite. The filter cake wasrinsed with CH₂Cl₂ (10 mL), and the combined organic extracts wereconcentrated under reduced pressure to provide the crude product2′-ethoxy-2,4-dinitro-biphenyl (0.95 g, 82%). No further purificationwas performed. ¹H NMR (300 MHz, CDCl₃) δ 8.75 (s, 1H), 8.43 (d, J=8.7Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.40 (t, J=7.8 Hz, 1H), 7.31 (d, J=7.5Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.88 (d, J=8.4 Hz, 1H), 3.44 (q, J=6.6Hz, 2H), 1.24 (t, J=6.6 Hz, 3H); HPLC ret. time 3.14 min, 10-100% CH₃CN,5 min gradient.

2′-Ethoxy-2-nitrobiphenyl-4-yl amine

A clear orange-red solution of polysulfide (120 ml, 7.5 eq.), previouslyprepared by heating sodium sulfide monohydrate (10 g), sulfur (1.04 g)and water (160 ml), was added dropwise at 90° C. over 45 minutes to asuspension of 2′-ethoxy-2,4-dinitro-biphenyl (1.2 g, 4.0 mmol) in water(40 ml). The red-brown solution was heated at reflux for 1.5 h. Themixture was cooled to room temperature, and solid NaCl (5 g) was added.The solution was extracted with CH₂Cl₂ (3×50 mL), and the combinedorganic extracts was concentrated to provide2′-ethoxy-2-nitrobiphenyl-4-yl amine (0.98 g, 95%) that was used in thenext step without further purification. ¹H NMR (300 MHz, CDCl₃) δ 7.26(m, 2H), 7.17 (d, J=2.7 Hz, 1H), 7.11 (d, J=7.8 Hz, 1H), 7.00 (t, J=6.9Hz, 1H), 6.83 (m, 2H), 3.91 (q, J=6.9 Hz, 2H), 1.23 (t, J=7.2 Hz, 3H);HPLC ret. time 2.81 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 259.1 m/z(MH⁺).

(2′-Ethoxy-2-nitrobiphenyl-4-yl)-carbamic acid tert-butyl ester

A mixture of 2′-ethoxy-2-nitrobipenyl-4-yl amine (0.98 g, 4.0 mmol) andBoc₂O (2.6 g, 12 mmol) was heated with a heat gun. Upon the consumptionof the starting material as indicated by TLC, the crude mixture waspurified by flash chromatography (silica gel, CH₂Cl₂) to provide(2′-ethoxy-2-nitrobiphenyl-4-yl)-carbamic acid tert-butyl ester (1.5 g,83%). ¹H NMR (300 MHz, CDCl₃) δ 7.99 (s, 1H), 7.55 (d, J=8.4 Hz, 1H),7.25 (m, 3H), 6.99 (t, J=7.5 Hz, 1H), 6.82 (m, 2H), 3.88 (q, J=6.9 Hz,2H), 1.50 (s, 9H), 1.18 (t, J=6.9 Hz, 3H); HPLC ret. time 3.30 min,10-100% CH₃CN, 5 min gradient.

D-18; (2′-ethoxy-2-aminobiphenyl-4-yl)-carbamic acid tert-butyl ester

To a solution of NiCl₂.6H₂O (0.26 g, 1.1 mmol) in EtOH (5 mL) was addedNaBH₄ (40 mg, 1.1 mmol) at −10° C. Gas evolution was observed and ablack precipitate was formed. After stirring for 5 min, a solution of2′-ethoxy-2-nitrobiphenyl-4-yl)carbamic acid tert-butyl ester (0.50 g,1.1 mmol) in EtOH (2 mL) was added. Additional NaBH₄ (80 mg, 60 mmol)was added in 3 portions over 20 min. The reaction was stirred at 0° C.for 20 min followed by the addition of NH₄OH (4 mL, 25% aq. solution).The resulting solution was stirred for 20 min. The crude mixture wasfiltered through a short plug of silica. The silica cake was flushedwith 5% MeOH in CH₂Cl₂ (10 mL), and the combined organic extracts wasconcentrated under reduced pressure to provide(2′-ethoxy-2-aminobiphenyl-4-yl)-carbamic acid tert-butyl ester (D-18)(0.36 g, quant.), which was used without further purification. HPLC ret.time 2.41 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 329.3 m/z (MH⁺).

Example 7

D-19; N-(3-Amino-5-trifluoromethyl-phenyl)-methanesulfonamide

A solution of 5-trifluoromethyl-benzene-1,3-diamine (250 mg, 1.42 mmol)in pyridine (0.52 mL) and CH₂Cl₂ (6.5 mL) was cooled to 0° C.Methanesulfonyl chloride (171 mg, 1.49 mmol) was slowly added at such arate that the temperature of the solution remained below 10° C. Themixture was stirred at 8° C. and then allowed to warm to roomtemperature after 30 min. After stirring at room temperature for 4 h,reaction was almost complete as indicated by LCMS analysis. The reactionmixture was quenched with sat. aq. NH₄Cl (10 mL) solution, extractedwith CH₂Cl₂ (4×10 mL), dried over Na₂SO₄, filtered, and concentrated toyield N-(3-amino-5-trifluoromethyl-phenyl)-methanesulfonamide (D-19) asa reddish semisolid (0.35 g, 97%), which was used without furtherpurification. ¹H-NMR (CDCl₃, 300 MHz) δ 6.76 (m, 1H), 6.70 (m, 1H), 6.66(s, 1H), 3.02 (s, 3H); ESI-MS 255.3 m/z (MH⁺).

Cyclic Amines

Example 1

7-Nitro-1,2,3,4-tetrahydro-quinoline

To a mixture of 1,2,3,4-tetrahydro-quinoline (20.0 g, 0.15 mol)dissolved in H₂SO₄ (98%, 150 mL), KNO₃ (18.2 g, 0.18 mol) was slowlyadded at 0° C. The reaction was allowed to warm to room temperature andstirred over night. The mixture was then poured into ice-water andbasified with sat. NaHCO₃ solution to pH 8. After extraction withCH₂Cl₂, the combined organic layers were washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography (petroleum ether-EtOAc, 10:1) to give7-nitro-1,2,3,4-tetrahydro-quinoline (6.6 g, 25%).

7-Nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester

A mixture of 7-nitro-1,2,3,4-tetrahydro-quinoline (4.0 g, 5.61 mmol),Boc₂O (1.29 g, 5.89 mmol) and DMAP (0.4 g) in CH₂Cl₂ was stirred at roomtemperature overnight. After diluted with water, the mixture wasextracted with CH₂Cl₂. The combined organic layers were washed withNaHCO₃ and brine, dried over Na₂SO₄ and concentrated to provide crude7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester thatwas used in the next step without further purification.

DC-1; tert-Butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate

A suspension of the crude 7-nitro-3,4-dihydro-2H-quinoline-1-carboxylicacid tert-butyl ester (4.5 g, 16.2 mol) and 10% Pd—C (0.45 g) in MeOH(40 mL) was stirred under H₂ (1 atm) at room temperature overnight.After filtration, the filtrate was concentrated and the residue waspurified by column chromatography (petroleum ether-EtOAc, 5:1) to givetert-butyl 7-amino-3,4-dihydroquinoline-1(2H)-carboxylate (DC-1) as abrown solid (1.2 g, 22% over 2 steps). ¹H NMR (CDCl₃) δ 7.15 (d, J=2 Hz,1H), 6.84 (d, J=8 Hz, 1H), 6.36-6.38 (m, 1H), 3.65-3.68 (m, 2H), 3.10(br s, 2H), 2.66 (t, J=6.4 Hz, 2H), 1.84-1.90 (m, 2H), 1.52 (s, 9H);ESI-MS 496.8 m/z (2M+H⁺).

Example 2

3-(2-Hydroxy-ethyl)-1,3-dihydro-indol-2-one

A stirring mixture of oxindole (5.7 g, 43 mmol) and Raney nickel (10 g)in ethane-1,2-diol (100 mL) was heated in an autoclave. After thereaction was complete, the mixture was filtered and the excess of diolwas removed under vacuum. The residual oil was triturated with hexane togive 3-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one as a colorlesscrystalline solid (4.6 g, 70%).

1,2-Dihydro-3-spiro-1′-cyclopropyl-1H-indole-2-one

To a solution of 3-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (4.6 g, 26mmol) and triethylamine (10 mL) in CH₂Cl₂ (100 mL) was added MsCl (3.4g, 30 mmol) dropwise at −20° C. The mixture was then allowed to warm upto room temperature and stirred overnight. The mixture was filtered andthe filtrate was concentrated under vacuum. The residue was purified bycolumn chromatography to give crude1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-2-one as a yellow solid(2.5 g), which was used directly in the next step.

1,2-Dihydro-3-spiro-1′-cyclopropyl-1H-indole

To a solution of 1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole-2-one (2.5g crude) in THF (50 mL) was added LiAlH₄ (2 g, 52 mmol) portionwise.After heating the mixture to reflux, it was poured into crushed ice,basified with aqueous ammonia to pH 8 and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give the crude1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole as a yellow solid (about 2g), which was used directly in the next step.

6-Nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

To a cooled solution (−5° C. to −10° C.) of NaNO₃ (1.3 g, 15.3 mmol) inH₂SO₄ (98%, 30 mL) was added1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (2 g, crude) dropwise overa period of 20 min. After addition, the reaction mixture was stirred foranother 40 min and poured over crushed ice (20 g). The cooled mixturewas then basified with NH₄OH and extracted with EtOAc. The organic layerwas washed with brine, dried over Na₂SO₄, and concentrated under reducedpressure to yield 6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indoleas a dark gray solid (1.3 g)

1-Acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

NaHCO₃ (5 g) was suspended in a solution of6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (1.3 g, crude) inCH₂Cl₂ (50 mL). While stirring vigorously, acetyl chloride (720 mg) wasadded dropwise. The mixture was stirred for 1 h and filtered. Thefiltrate was concentrated under vacuum. The residue was purified byflash column chromatography on silica gel to give1-acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (0.9 g,15% over 4 steps).

DC-2; 1-Acetyl-6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole

A mixture of1-acetyl-6-nitro-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (383 mg, 2mmol) and Pd—C (10%, 100 mg) in EtOH (50 mL) was stirred at roomtemperature under H₂ (1 atm) for 1.5 h. The catalyst was filtered offand the filtrate was concentrated under reduced pressure. The residuewas treated with HCl/MeOH to give1-acetyl-6-amino-1,2-dihydro-3-spiro-1′-cyclopropyl-1H-indole (DC-2)(300 mg, 90%) as a hydrochloride salt.

Example 3

3-Methyl-but-2-enoic acid phenylamide

A mixture of 3-methyl-but-2-enoic acid (100 g, 1 mol) and SOCl₂ (119 g,1 mol) was heated at reflux for 3 h. The excess SOCl₂ was removed underreduced pressure. CH₂Cl₂ (200 mL) was added followed by the addition ofaniline (93 g, 1.0 mol) in Et₃N (101 g, 1 mol) at 0° C. The mixture wasstirred at room temperature for 1 h and quenched with HCl (5%, 150 mL).The aqueous layer was separated and extracted with CH₂Cl₂. The combinedorganic layers were washed with water (2×100 mL) and brine (100 mL),dried over Na₂SO₄ and concentrated to give 3-methyl-but-2-enoic acidphenylamide (120 g, 80%).

4,4-Dimethyl-3,4-dihydro-1H-quinolin-2-one

AlCl₃ (500 g, 3.8 mol) was carefully added to a suspension of3-methyl-but-2-enoic acid phenylamide (105 g, 0.6 mol) in benzene (1000mL). The reaction mixture was stirred at 80° C. overnight and pouredinto ice-water. The organic layer was separated and the aqueous layerwas extracted with ethyl acetate (250 mL×3). The combined organic layerswere washed with water (200 mL×2) and brine (200 mL), dried over Na₂SO₄and concentrated to give 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (90g, 86%).

4,4-Dimethyl-1,2,3,4-tetrahydro-quinoline

A solution of 4,4-dimethyl-3,4-dihydro-1H-quinolin-2-one (35 g, 0.2 mol)in THF (100 mL) was added dropwise to a suspension of LiAlH₄ (18 g, 0.47mol) in THF (200 mL) at 0° C. After addition, the mixture was stirred atroom temperature for 30 min and then slowly heated to reflux for 1 h.The mixture was then cooled to 0° C. Water (18 mL) and NaOH solution(10%, 100 mL) were carefully added to quench the reaction. The solid wasfiltered off and the filtrate was concentrated to give4,4-dimethyl-1,2,3,4-tetrahydro-quinoline.

4,4-Dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline

To a mixture of 4,4-dimethyl-1,2,3,4-tetrahydro-quinoline (33 g, 0.2mol) in H₂SO₄ (120 mL) was slowly added KNO₃ (20.7 g, 0.2 mol) at 0° C.After addition, the mixture was stirred at room temperature for 2 h,carefully poured into ice water and basified with Na₂CO₃ to pH 8. Themixture was extracted with ethyl acetate (3×200 mL). The combinedextracts were washed with water and brine, dried over Na₂SO₄ andconcentrated to give 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline(21 g, 50%).

4,4-Dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester

A mixture of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline (25 g,0.12 mol) and Boc₂O (55 g, 0.25 mol) was stirred at 80° C. for 2 days.The mixture was purified by silica gel chromatography to give4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1-carboxylic acidtert-butyl ester (8 g, 22%).

DC-3; tert-Butyl7-amino-3,4-dihydro-4,4-dimethylquinoline-1(2H)-carboxylate

A mixture of 4,4-dimethyl-7-nitro-3,4-dihydro-2H-quinoline-1 carboxylicacid tert-butyl ester (8.3 g, 0.03 mol) and Pd—C (0.5 g) in methanol(100 mL) was stirred under H₂ (1 atm) at room temperature overnight. Thecatalyst was filtered off and the filtrate was concentrated. The residuewas washed with petroleum ether to give tert-butyl7-amino-3,4-dihydro-4,4-dimethylquinoline-1(2H)-carboxylate (DC-3) (7.2g, 95%). ¹H NMR (CDCl₃) δ 7.11-7.04 (m, 2H), 6.45-6.38 (m, 1H),3.71-3.67 (m, 2H), 3.50-3.28 (m, 2H), 1.71-1.67 (m, 2H), 1.51 (s, 9H),1.24 (s, 6H).

Example 4

1-Chloro-4-methylpentan-3-one

Ethylene was passed through a solution of isobutyryl chloride (50 g, 0.5mol) and AlCl₃ (68.8 g, 0.52 mol) in anhydrous CH₂Cl₂ (700 mL) at 5° C.After 4 h, the absorption of ethylene ceased, and the mixture wasstirred at room temperature overnight. The mixture was poured into colddiluted HCl solution and extracted with CH₂Cl₂. The combined organicphases were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the crude 1-chloro-4-methylpentan-3-one, which wasused directly in the next step without further purification.

4-Methyl-1-(phenylamino)-pentan-3-one

A suspension of the crude 1-chloro-4-methylpentan-3-one (about 60 g),aniline (69.8 g, 0.75 mol) and NaHCO₃ (210 g, 2.5 mol) in CH₃CN (1000mL) was heated at reflux overnight. After cooling, the insoluble saltwas filtered off and the filtrate was concentrated. The residue wasdiluted with CH₂Cl₂, washed with 10% HCl solution (100 mL) and brine,dried over Na₂SO₄, filtered and concentrated to give the crude4-methyl-1-(phenylamino)-pentan-3-one.

4-Methyl-1-(phenylamino)-pentan-3-ol

At −10° C., NaBH₄ (56.7 g, 1.5 mol) was gradually added to a mixture ofthe crude 4-methyl-1-(phenylamino)-pentan-3-one (about 80 g) in MeOH(500 mL). After addition, the reaction mixture was allowed to warm toroom temperature and stirred for 20 min. The solvent was removed and theresidue was repartitioned between water and CH₂Cl₂. The organic phasewas separated, washed with brine, dried over Na₂SO₄, filtered andconcentrated. The resulting gum was triturated with ether to give4-methyl-1-(phenylamino)-pentan-3-ol as a white solid (22 g, 23%).

5,5-Dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine

A mixture of 4-methyl-1-(phenylamino)-pentan-3-ol (22 g, 0.11 mol) in98% H₂SO₄ (250 mL) was stirred at 50° C. for 30 min. The reactionmixture was poured into ice-water basified with sat. NaOH solution to pH8 and extracted with CH₂Cl₂. The combined organic phases were washedwith brine, dried over Na₂SO₄, filtered and concentrated. The residuewas purified by column chromatography (petroleum ether) to afford5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine as a brown oil (1.5g, 8%).

5,5-Dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine

At 0° C., KNO₃ (0.76 g, 7.54 mmol) was added portionwise to a solutionof 5,5-dimethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.1 g, 6.28 mmol)in H₂SO₄ (15 mL). After stirring 15 min at this temperature, the mixturewas poured into ice water, basified with sat. NaHCO₃ to pH 8 andextracted with EtOAc. The organic layer was washed with brine, driedover Na₂SO₄ and concentrated to give crude5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g),which was used directly in the next step without further purification.

1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone

Acetyl chloride (0.77 mL, 11 mmol) was added to a suspension of crude5,5-dimethyl-8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.2 g, 5.45mmol) and NaHCO₃ (1.37 g, 16.3 mmol) in CH₂Cl₂ (20 mL). The mixture washeated at reflux for 1 h. After cooling, the mixture was poured intowater and extracted with CH₂Cl₂. The organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bycolumn chromatography to afford1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone(1.05 g, 64% over two steps).

DC-4;1-(8-Amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)ethanone

A suspension of1-(5,5-dimethyl-8-nitro-2,3,4,5-tetrahydrobenzo[b]azepin-1-yl)ethanone(1.05 g, 40 mmol) and 10% Pd—C (0.2 g) in MeOH (20 mL) was stirred underH₂ (1 atm) at room temperature for 4 h. After filtration, the filtratewas concentrated to give1-(8-amino-2,3,4,5-tetrahydro-5,5-dimethylbenzo[b]azepin-1-yl)ethanoneas a white solid (DC-4) (880 mg, 94%). ¹H NMR (CDCl₃) δ 7.06 (d, J=8.0Hz, 1H), 6.59 (dd, J=8.4, 2.4 Hz, 1H), 6.50 (br s, 1H), 4.18-4.05 (m,1H), 3.46-3.36 (m, 1H), 2.23 (s, 3H), 1.92-1.85 (m, 1H), 1.61-1.51 (m,3H), 1.21 (s, 3H), 0.73 (t, J=7.2 Hz, 3H); ESI-MS 233.0 m/z (MH⁺).

Example 5

Spiro[1H-indene-1,4′-piperidin]-3(2H)-one, 1′-benzyl

A mixture of spiro[1H-indene-1,4′-piperidine]-1′-carboxylic acid,2,3-dihydro-3-oxo-, 1,1-dimethylethyl ester (9.50 g, 31.50 mmol) insaturated HCl/MeOH (50 mL) was stirred at 25° C. overnight. The solventwas removed under reduced pressure to yield an off-white solid (7.50 g).To a solution of this solid in dry CH₃CN (30 mL) was added anhydrousK₂CO₃ (7.85 g, 56.80 mmol). The suspension was stirred for 5 min, andbenzyl bromide (5.93 g, 34.65 mmol) was added dropwise at roomtemperature. The mixture was stirred for 2 h, poured into cracked iceand extracted with CH₂Cl₂. The combined organic layers were dried overNa₂SO₄ and concentrated under vacuum to give crudespiro[1H-indene-1,4′-piperidin]-3(2H)-one, 1′-benzyl (7.93 g, 87%),which was used without further purification.

Spiro[1H-indene-1,4′-piperidin]-3(2H)-one, 1′-benzyl, oxime

To a solution of spiro[1H-indene-1,4′-piperidin]-3(2H)-one, 1′-benzyl(7.93 g, 27.25 mmol) in EtOH (50 mL) were added hydroxylaminehydrochloride (3.79 g, 54.50 mmol) and anhydrous sodium acetate (4.02 g,49.01 mmol) in one portion. The mixture was refluxed for 1 h, and thencooled to room temperature. The solvent was removed under reducedpressure and 200 mL of water was added. The mixture was extracted withCH₂Cl₂. The combined organic layers were dried over Na₂SO₄ andconcentrated to yield spiro[1H-indene-1,4′-piperidin]-3(2H)-one,1′-benzyl, oxime (7.57 g, 91%), which was used without furtherpurification.

1,2,3,4-Tetrahydroquinolin-4-spiro-4′-(N′-benzyl-piperidine)

To a solution of spiro[1H-indene-1,4′-piperidin]-3(2H)-one, 1′-benzyl,oxime (7.57 g, 24.74 mmol) in dry CH₂Cl₂ (150 mL) was added dropwiseDIBAL-H (135.7 mL, IM in toluene) at 0° C. The mixture was stirred at 0°C. for 3 h, diluted with CH₂Cl₂ (100 mL), and quenched with NaF (20.78g, 495 mmol) and water (6.7 g, 372 mmol). The resulting suspension wasstirred vigorously at 0° C. for 30 min. After filtration, the residuewas washed with CH₂Cl₂. The combined filtrates were concentrated undervacuum to give an off-brown oil that was purified by columnchromatography on silica gel (CH₂Cl₂-MeOH, 30:1) to afford1,2,3,4-tetrahydroquinolin-4-spiro-4′-(N′-benzyl-piperidine) (2.72 g,38%).

1,2,3,4-Tetrahydroquinolin-4-spiro-4′-piperidine

A suspension of1,2,3,4-Tetrahydroquinolin-4-spiro-4′-(N′-benzyl-piperidine) (300 mg,1.03 mmol) and Pd(OH)₂—C (30 mg) in MeOH (3 mL) was stirred under H₂ (55psi) at 50° C. over night. After cooling, the catalyst was filtered offand washed with MeOH. The combined filtrates were concentrated underreduced pressure to yield1,2,3,4-tetrahydroquinolin-4-spiro-4′-piperidine as a white solid (176mg, 85%), which was used without further purification.

7′-Nitro-spiro[piperidine-4,4′(1′H)-quinoline], 2′,3′-dihydro-carboxylicacid tert-butyl ester

KNO₃ (69.97 mg, 0.69 mmol) was added portion-wise to a suspension of1,2,3,4-tetrahydroquinolin-4-spiro-4′-piperidine (133 mg, 0.66 mmol) in98% H₂SO₄ (2 mL) at 0° C. After the addition was complete, the reactionmixture was allowed to warm to room temperature and stirred foradditional 2 h. The mixture was then poured into cracked ice andbasified with 10% NaOH to pH 8. Boc₂O (172 mg, 0.79 mmol) was addeddropwise and the mixture was stirred at room temperature for 1 h. Themixture was then extracted with EtOAc and the combined organic layerswere dried over Na₂SO₄, filtered and concentrated to yield crude7′-nitro-spiro[piperidine-4,4′(1′H)-quinoline], 2′,3′-dihydro-carboxylicacid tert-butyl ester (230 mg), which was used in the next step withoutfurther purification.

7′-nitro-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester

Acetyl chloride (260 mg, 3.30 mmol) was added dropwise to a suspensionof 7′-nitro-spiro[piperidine-4,4′(1′H)-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester (230 mg) and NaHCO₃ (1.11g, 13.17 mmol) in MeCN (5 mL) at room temperature. The reaction mixturewas refluxed for 4 h. After cooling, the suspension was filtered and thefiltrate was concentrated. The residue was purified by columnchromatography (petroleum ether-EtOAc, 10:1) to provide7′-nitro-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester (150 mg, 58% over 2steps)

DC-5; 7′-Amino-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester

A suspension of 7′-nitro-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester (150 mg, 0.39 mmol) andRaney Ni (15 mg) in MeOH (2 mL) was stirred under H₂ (1 atm) at 25° C.overnight. The catalyst was removed via filtration and washed with MeOH.The combined filtrates were dried over Na₂SO₄, filtered, andconcentrated to yield7′-amino-spiro[piperidine-4,4′(1′H)-1-acetyl-quinoline],2′,3′-dihydro-carboxylic acid tert-butyl ester (DC-5) (133 mg, 96%).

Example 7

2-(2,4-Dinitrophenylthio)-acetic acid

Et₃N (1.5 g, 15 mmol) and mercapto-acetic acid (1 g, 11 mmol) were addedto a solution of 1-chloro-2,4-dinitrobenzene (2.26 g, 10 mmol) in1,4-dioxane (50 mL) at room temperature. After stirring at roomtemperature for 5 h, H₂O (100 mL) was added. The resulting suspensionwas extracted with ethyl acetate (100 mL×3). The ethyl acetate extractwas washed with water and brine, dried over Na₂SO₄ and concentrated togive 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 74%), which was usedwithout further purification.

DC-7; 6-Amino-2H-benzo[b][1,4]thiazin-3(4H)-one

A solution of 2-(2,4-dinitrophenylthio)-acetic acid (2.3 g, 9 mmol) andtin (II) chloride dihydrate (22.6 g, 0.1 mol) in ethanol (30 mL) wasrefluxed overnight. After removal of the solvent under reduced pressure,the residual slurry was diluted with water (100 mL) and basified with10% Na₂CO₃ solution to pH 8. The resulting suspension was extracted withethyl acetate (3×100 mL). The ethyl acetate extract was washed withwater and brine, dried over Na₂SO₄, and concentrated. The residue waswashed with CH₂Cl₂ to yield 6-amino-2H-benzo[b][1,4]thiazin-3(4H)-one(DC-7) as a yellow powder (1 g, 52%). ¹H NMR (DMSO-d₆) δ 10.24 (s, 1H),6.88 (d, 1H, J=6 Hz), 6.19-6.21 (m, 2H), 5.15 (s, 2H), 3.28 (s, 2H);ESI-MS 181.1 m/z (MH⁺).

Example 7

N-(2-Bromo-5-nitrophenyl)acetamide

Acetic anhydride (1.4 mL, 13.8 mmol) was added dropwise to a stirringsolution of 2-bromo-5-nitroaniline (3 g, 13.8 mmol) in glacial aceticacid (30 mL) at 25° C. The reaction mixture was stirred at roomtemperature overnight, and then poured into water. The precipitate wascollected via filtration, washed with water and dried under vacuum toprovide N-(2-bromo-5-nitrophenyl)acetamide as an off white solid (3.6 g,90%).

N-(2-Bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide

At 25° C., a solution of 3-bromo-2-methylpropene (3.4 g, 55.6 mmol) inanhydrous DMF (30 mL) was added dropwise to a solution ofN-(2-bromo-5-nitrophenyl)acetamide (3.6 g, 13.9 mmol) and potassiumcarbonate (3.9 g, 27.8 mmol) in anhydrous DMF (50 mL). The reactionmixture was stirred at 25° C. overnight. The reaction mixture was thenfiltered and the filtrate was treated with sat. Na₂CO₃ solution. Theorganic layer was separated and the aqueous layer was extracted withEtOAc. The combined organic extracts were washed with water and brine,dried over MgSO₄, filtered and concentrated under vacuum to provideN-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide as a goldensolid (3.1 g, 85%). ESI-MS 313 m/z (MH⁺).

1-(3,3-Dimethyl-6-nitroindolin-1-yl)ethanone

A solution of N-(2-bromo-5-nitrophenyl)-N-(2-methylprop-2-enyl)acetamide(3.1 g, 10.2 mmol), tetraethylammonium chloride hydrate (2.4 g, 149mmol), sodium formate (1.08 g, 18 mmol), sodium acetate (2.76 g, 34.2mmol) and palladium acetate (0.32 g, 13.2 mmol) in anhydrous DMF (50 mL)was stirred at 80° C. for 15 h under N₂ atmosphere. After cooling, themixture was filtered through Celite. The Celite was washed with EtOAcand the combined filtrates were washed with sat. NaHCO₃. The separatedorganic layer was washed with water and brine, dried over MgSO₄,filtered and concentrated under reduced pressure to provide1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone as a brown solid (2.1 g,88%).

DC-8; 1-(6-Amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone

10% Pd—C (0.2 g) was added to a suspension of1-(3,3-dimethyl-6-nitroindolin-1-yl)ethanone (2.1 g, 9 mmol) in MeOH (20mL). The reaction was stirred under H₂ (40 psi) at room temperatureovernight. Pd—C was filtered off and the filtrate was concentrated undervacuum to give a crude product, which was purified by columnchromatography to yield1-(6-amino-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (DC-8) (1.3 g,61%).

Example 8

2,3,4,5-Tetrahydro-1H-benzo[b]azepine

DIBAL (90 mL, 90 mmol) was added dropwise to a solution of4-dihydro-2H-naphthalen-1-one oxime (3 g, 18 mmol) in dichloromethane(50 mL) at 0° C. The mixture was stirred at this temperature for 2 h.The reaction was quenched with dichloromethane (30 mL), followed bytreatment with NaF (2 g. 0.36 mol) and H₂O (5 mL, 0.27 mol). Vigorousstirring of the resulting suspension was continued at 0° C. for 30 min.After filtration, the filtrate was concentrated. The residue waspurified by flash column chromatography to give2,3,4,5-tetrahydro-1H-benzo[b]azepine as a colorless oil (1.9 g, 70%).

8-Nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine

At −10° C., 2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.9 g, 13 mmol) wasadded dropwise to a solution of KNO₃ (3 g, 30 mmol) in H₂SO₄ (50 mL).The mixture was stirred for 40 min, poured over crushed ice, basifiedwith aq. ammonia to pH 13, and extracted with EtOAc. The combinedorganic phases were washed with brine, dried over Na₂SO₄ andconcentrated to give 8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine as ablack solid (1.3 g, 51%), which was used without further purification.

1-(8-Nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone

Acetyl chloride (1 g, 13 mmol) was added dropwise to a mixture of8-nitro-2,3,4,5-tetrahydro-1H-benzo[b]azepine (1.3 g, 6.8 mmol) andNaHCO₃ (1 g, 12 mmol) in CH₂Cl₂ (50 mL). After stirring for 1 h, themixture was filtered and the filtrate was concentrated. The residue wasdissolved in CH₂Cl₂, washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by column chromatography to give1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone as a yellowsolid (1.3 g, 80%).

DC-9; 1-(8-Amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone

A mixture of 1-(8-nitro-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone(1.3 g, 5.4 mmol) and Pd—C (10%, 100 mg) in EtOH (200 mL) was stirredunder H₂ (1 atm) at room temperature for 1.5 h. The mixture was filteredthrough a layer of Celite and the filtrate was concentrated to give1-(8-amino-2,3,4,5-tetrahydro-benzo[b]azepin-1-yl)-ethanone (DC-9) as awhite solid (1 g, 90%). ¹H NMR (CDCl₃) δ 7.01 (d, J=6.0 Hz, 1H), 6.56(dd, J=6.0, 1.8 Hz, 1H), 6.50 (d, J=1.8 Hz, 1H), 4.66-4.61 (m, 1H), 3.50(br s, 2H), 2.64-2.55 (m, 3H), 1.94-1.91 (m, 5H), 1.77-1.72 (m, 1H),1.32-1.30 (m, 1H); ESI-MS 204.1 m/z (MH⁺).

Example 9

6-Nitro-4H-benzo[1,4]oxazin-3-one

At 0° C., chloroacetyl chloride (8.75 mL, 0.11 mol) was added dropwiseto a mixture of 4-nitro-2-aminophenol (15.4 g, 0.1 mol),benzyltrimethylammonium chloride (18.6 g, 0.1 mol) and NaHCO₃ (42 g, 0.5mol) in chloroform (350 ml) over a period of 30 min. After addition, thereaction mixture was stirred at 0° C. for 1 h, then at 50° C. overnight.The solvent was removed under reduced pressure and the residue wastreated with water (50 ml). The solid was collected via filtration,washed with water and recrystallized from ethanol to provide6-nitro-4H-benzo[1,4]oxazin-3-one as a pale yellow solid (8 g, 41%).

6-Nitro-3,4-dihydro-2H-benzo[1,4]oxazine

A solution of BH₃.Me₂S in THF (2 M, 7.75 mL, 15.5 mmol) was addeddropwise to a suspension of 6-nitro-4H-benzo[1,4]oxazin-3-one (0.6 g,3.1 mmol) in THF (10 mL). The mixture was stirred at room temperatureovernight. The reaction was quenched with MeOH (5 mL) at 0° C. and thenwater (20 mL) was added. The mixture was extracted with Et₂O and thecombined organic layers were washed with brine, dried over Na₂SO₄ andconcentrated to give 6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a redsolid (0.5 g, 89%), which was used without further purification.

4-Acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine

Under vigorous stirring at room temperature, acetyl chloride (1.02 g, 13mmol) was added dropwise to a mixture of6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.8 g, 10 mmol) and NaHCO₃(7.14 g, 85 mmol) in CH₂Cl₂ (50 mL). After addition, the reaction wasstirred for 1 h at this temperature. The mixture was filtered and thefiltrate was concentrated under vacuum. The residue was treated withEt₂O:hexane (1:2, 50 mL) under stirring for 30 min and then filtered togive 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine as a pale yellowsolid (2 g, 90%).

DC-10; 4-Acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazine

A mixture of 4-acetyl-6-nitro-3,4-dihydro-2H-benzo[1,4]oxazine (1.5 g,67.6 mmol) and Pd—C (10%, 100 mg) in EtOH (30 mL) was stirred under H₂(1 atm) overnight. The catalyst was filtered off and the filtrate wasconcentrated. The residue was treated with HCl/MeOH to give4-acetyl-6-amino-3,4-dihydro-2H-benzo[1,4]oxazine hydrochloride (DC-10)as an off-white solid (1.1 g, 85%). ¹H NMR (DMSO-d₆) δ 10.12 (br s, 2H),8.08 (br s, 1H), 6.90-7.03 (m, 2H), 4.24 (t, J=4.8 Hz, 2H), 3.83 (t,J=4.8 Hz, 2H), 2.23 (s, 3H); ESI-MS 192.1 m/z (MH⁺).

Example 10

1,2,3,4-Tetrahydro-7-nitroisoquinoline hydrochloride

1,2,3,4-Tetrahydroisoquinoline (6.3 mL, 50.0 mmol) was added dropwise toa stirred ice-cold solution of concentrated H₂SO₄ (25 mL). KNO₃ (5.6 g,55.0 mmol) was added portionwise while maintaining the temperature below5° C. The mixture was stirred at room temperature overnight, carefullypoured into an ice-cold solution of concentrated NH₄OH, and thenextracted three times with CHCl₃. The combined organic layers werewashed with brine, dried over Na₂SO₄ and concentrated. The resultingdark brown oil was taken up into EtOH, cooled in an ice bath and treatedwith concentrated HCl. The yellow precipitate was collected viafiltration and recrystallized from methanol to give1,2,3,4-tetrahydro-7-nitroisoquinoline hydrochloride as yellow solid(2.5 g, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 2H), 8.22 (d, J=1.6Hz, 1H), 8.11 (dd, J=8.5, 2.2 Hz, 1H), 7.53 (d, J=8.5 Hz, 1H), 4.38 (s,2H), 3.38 (s, 2H), 3.17-3.14 (m, 2H); HPLC ret. time 0.51 min, 10-99%CH₃CN, 5 min run; ESI-MS 179.0 m/z (MH⁺).

tert-Butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate

A mixture of 1,2,3,4-Tetrahydro-7-nitroisoquinoline (2.5 g, 11.6 mmol),1,4-dioxane (24 mL), H₂O (12 mL) and 1N NaOH (12 mL) was cooled in anice-bath, and Boc₂O (2.8 g, 12.8 mmol) was added. The mixture wasstirred at room temperature for 2.5 h, acidified with a 5% KHSO₄solution to pH 2-3, and then extracted with EtOAc. The organic layer wasdried over MgSO₄ and concentrated to give tert-butyl3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, quant.), whichwas used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ 8.13(d, J=2.3 Hz, 1H), 8.03 (dd, J=8.4, 2.5 Hz, 1H), 7.45 (d, J=8.5 Hz, 1H),4.63 (s, 2H), 3.60-3.57 (m, 2H), 2.90 (t, J=5.9 Hz, 2H), 1.44 (s, 9H);HPLC ret. time 3.51 min, 10-99% CH₃CN, 5 min run; ESI-MS 279.2 m/z(MH⁺).

DC-6; tert-Butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate

Pd(OH)₂ (330.0 mg) was added to a stirring solution of tert-butyl3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, 12.0 mmol) inMeOH (56 mL) under N₂ atmosphere. The reaction mixture was stirred underH₂ (1 atm) at room temperature for 72 h. The solid was removed byfiltration through Celite. The filtrate was concentrated and purified bycolumn chromatography (15-35% EtOAc-Hexanes) to provide tert-butyl7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (DC-6) as a pink oil(2.0 g, 69%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.79 (d, J=8.1 Hz, 1H), 6.40(dd, J=8.1, 2.3 Hz, 1H), 6.31 (s, 1H), 4.88 (s, 2H), 4.33 (s, 2H), 3.48(t, J=5.9 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 1.42 (s, 9H); HPLC ret. time2.13 min, 10-99% CH₃CN, 5 min run; ESI-MS 249.0 m/z (MH⁺).

Other Amines

Example 1

4-Bromo-3-nitrobenzonitrile

To a solution of 4-bromobenzonitrile (4.0 g, 22 mmol) in conc. H₂SO₄ (10mL) was added dropwise at 0° C. nitric acid (6 mL). The reaction mixturewas stirred at 0° C. for 30 min, and then at room temperature for 2.5 h.The resulting solution was poured into ice-water. The white precipitatewas collected via filtration and washed with water until the washingswere neutral. The solid was recrystallized from an ethanol/water mixture(1:1, 20 mL) twice to afford 4-bromo-3-nitrobenzonitrile as a whitecrystalline solid (2.8 g, 56%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (s,1H), 8.06 (d, J=8.4 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H); ¹³C NMR (75 MHz,DMSO-d₆) δ 150.4, 137.4, 136.6, 129.6, 119.6, 117.0, 112.6; HPLC ret.time 1.96 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 227.1 m/z (MH⁺).

2′-Ethoxy-2-nitrobiphenyl-4-carbonitrile

A 50 mL round-bottom flask was charged with 4-bromo-3-nitrobenzonitrile(1.0 g 4.4 mmol), 2-ethoxyphenylboronic acid (731 mg, 4.4 mmol),Pd₂(dba)₃ (18 mg, 0.022 mmol) and potassium fluoride (786 mg, 13.5mmol). The reaction vessel was evacuated and filled with argon. Dry THF(300 mL) was added followed by the addition of P(t-Bu)₃ (0.11 mL, 10%wt. in hexane). The reaction mixture was stirred at room temperature for30 min., and then heated at 80° C. for 16 h. After cooling to roomtemperature, the resulting mixture was filtered through a Celite pad andconcentrated. 2′-Ethoxy-2-nitrobiphenyl-4-carbonitrile was isolated as ayellow solid (1.12 g, 95%). ¹H NMR (300 MHz, DMSO-d₆) δ 8.51 (s, 1H),8.20 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.4 Hz, 1H), 7.41 (t, J=8.4 Hz, 1H),7.37 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H),3.91 (q, J=7.2 Hz, 2H), 1.12 (t, J=7.2 Hz, 3H); ¹³C NMR (75 MHz,DMSO-d₆) δ 154.9, 149.7, 137.3, 137.2, 134.4, 131.5, 130.4, 128.4,125.4, 121.8, 117.6, 112.3, 111.9, 64.1, 14.7; HPLC ret. time 2.43 min,10-100% CH₃CN, 5 min gradient; ESI-MS 269.3 m/z (MH⁺).

4-Aminomethyl-2′-ethoxy-biphenyl-2-ylamine

To a solution of 2′-ethoxy-2-nitrobiphenyl-4-carbonitrile (500 mg, 1.86mmol) in THF (80 mL) was added a solution of BH₃.THF (5.6 mL, 10% wt. inTHF, 5.6 mmol) at 0° C. over 30 min. The reaction mixture was stirred at0° C. for 3 h and then at room temperature for 15 h. The reactionsolution was chilled to 0° C., and a H₂O/THF mixture (3 mL) was added.After being agitated at room temperature for 6 h, the volatiles wereremoved under reduced pressure. The residue was dissolved in EtOAc (100mL) and extracted with 1N HCl (2×100 mL). The aqueous phase was basifiedwith 1N NaOH solution to pH 1 and extracted with EtOAc (3×50 mL). Thecombined organic layers were washed with water (50 mL), dried overNa₂SO₄, filtered, and evaporated. After drying under vacuum,4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine was isolated as a brown oil(370 mg, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ 7.28 (dt, J=7.2 Hz, J=1.8 Hz,1H), 7.09 (dd, J=7.2 Hz, J=1.8 Hz, 1H), 7.05 (d, J=7.5 Hz, 1H), 6.96(dt, J=7.2 Hz, J=0.9 Hz, 1H), 6.83 (d, J=7.5 Hz, 1H), 6.66 (d, J=1.2 Hz,1H), 6.57 (dd, J=7.5 Hz, J=1.5 Hz, 1H), 4.29 (s, 2H), 4.02 (q, J=6.9 Hz,2H), 3.60 (s, 2H), 1.21 (t, J=6.9 Hz, 3H); HPLC ret. time 1.54 min,10-100% CH₃CN, 5 min gradient; ESI-MS 243.3 m/z (MH⁺).

E-1; (2-Amino-2′-ethoxy-biphenyl-4-ylmethyl)carbamic Acid tert-butylEster

A solution of Boc₂O (123 mg, 0.565 mmol) in 1,4-dioxane (10 mL) wasadded over a period of 30 min. to a solution of4-aminomethyl-2′-ethoxy-biphenyl-2-ylamine (274 mg, 1.13 mmol) in1,4-dioxane (10 mL). The reaction mixture was stirred at roomtemperature for 16 h. The volatiles were removed on a rotary evaporator.The residue was purified by flash chromatography (silica gel, EtOAc—CH₂Cl₂, 1:4) to afford (2-Amino-2′-ethoxy-biphenyl-4-ylmethyl)carbamicacid tert-butyl ester (E-1) as a pale yellow oil (119 mg, 31%). ¹H NMR(300 MHz, DMSO-d₆) δ 7.27 (m, 2H), 7.07 (dd, J=7.2 Hz, J=1.8 Hz, 1H),7.03 (d, J=7.8 Hz, 1H), 6.95 (dt, J=7.2 Hz, J=0.9 Hz, 1H), 6.81 (d,J=7.5 Hz, 1H), 6.55 (s, 1H), 6.45 (dd, J=7.8 Hz, J=1.5 Hz, 1H), 4.47 (s,2H), 4.00 (q, J=7.2 Hz, 2H), 1.38 (s, 9H), 1.20 (t, J=7.2 Hz, 3H); HPLCret. time 2.34 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 343.1 m/z(MH⁺).

Example 2

2-Bromo-1-tert-butyl-4-nitrobenzene

To a solution of 1-tert-butyl-4-nitrobenzene (8.95 g, 50 mmol) andsilver sulfate (10 g, 32 mmol) in 50 mL of 90% sulfuric acid was addeddropwise bromine (7.95 g, 50 mmol). Stirring was continued at roomtemperature overnight, and then the mixture was poured into dilutesodium hydrogen sulfite solution and was extracted with EtOAc threetimes. The combined organic layers were washed with brine and dried overMgSO₄. After filtration, the filtrate was concentrated to give2-bromo-1-tert-butyl-4-nitrobenzene (12.7 g, 98%), which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.47 (d, J=2.5Hz, 1H), 8.11 (dd, J=8.8, 2.5 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 1.57 (s,9H); HPLC ret. time 4.05 min, 10-100% CH₃CN, 5 min gradient.

2-tert-Butyl-5-nitrobenzonitrile

To a solution of 2-bromo-1-tert-butyl-4-nitrobenzene (2.13 g, 8.2 mmol)and Zn(CN)₂ (770 mg, 6.56 mmol) in DMF (10 mL) was added Pd(PPh₃)₄ (474mg, 0.41 mmol) under a nitrogen atmosphere. The mixture was heated in asealed vessel at 205° C. for 5 h. After cooling to room temperature, themixture was diluted with water and extracted with EtOAc twice. Thecombined organic layers were washed with brine and dried over MgSO₄.After removal of solvent, the residue was purified by columnchromatography (0-10% EtOAc-Hexane) to give2-tert-butyl-5-nitrobenzonitrile (1.33 g, 80%). ¹H NMR (400 MHz, CDCl₃)δ 8.55 (d, J=2.3 Hz, 1H), 8.36 (dd, J=8.8, 2.2 Hz, 1H), 7.73 (d, J=8.9Hz, 1H), 1.60 (s, 9H); HPLC ret. time 3.42 min, 10-100% CH₃CN, 5 mingradient.

E-2; 2-tert-Butyl-5-aminobenzonitrile

To a refluxing solution of 2-tert-butyl-5-nitrobenzonitrile (816 mg, 4.0mmol) in EtOH (20 mL) was added ammonium formate (816 mg, 12.6 mmol),followed by 10% Pd—C (570 mg). The reaction mixture was refluxed foradditional 90 min, cooled to room temperature and filtered throughCelite. The filtrate was concentrated to give2-tert-butyl-5-aminobenzonitrile (E-2) (630 mg, 91%), which was usedwithout further purification. HPLC ret. time 2.66 min, 10-99% CH₃CN, 5min run; ESI-MS 175.2 m/z (MH⁺).

Example 3

(2-tert-Butyl-5-nitrophenyl)methanamine

To a solution of 2-tert-butyl-5-nitrobenzonitrile (612 mg, 3.0 mmol) inTHF (10 mL) was added a solution of BH₃.THF (12 mL, 1M in THF, 12.0mmol) under nitrogen. The reaction mixture was stirred at 70° C.overnight and cooled to 0° C. Methanol (2 mL) was added followed by theaddition of 1N HCl (2 mL). After refluxing for 30 min, the solution wasdiluted with water and extracted with EtOAc. The aqueous layer wasbasified with 1N NaOH and extracted with EtOAc twice. The combinedorganic layers were washed with brine and dried over Mg₂SO₄. Afterremoval of solvent, the residue was purified by column chromatography(0-10% MeOH—CH₂Cl₂) to give (2-tert-butyl-5-nitrophenyl)methanamine (268mg, 43%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=2.7 Hz, 1H), 7.99 (dd,J=8.8, 2.8 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 4.03 (s, 2H), 2.00 (t, J=2.1Hz, 2H), 1.40 (s, 9H); HPLC ret. time 2.05 min, 10-100% CH₃CN, 5 mingradient; ESI-MS 209.3 m/z (MH⁺).

tert-Butyl 2-tert-butyl-5-nitrobenzylcarbamate

A solution of (2-tert-butyl-5-nitrophenyl)methanamine (208 mg, 1 mmol)and Boc₂O (229 mg, 1.05 mmol) in THF (5 mL) was refluxed for 30 min.After cooling to room temperature, the solution was diluted with waterand extracted with EtOAc. The combined organic layers were washed withbrine and dried over MgSO₄. After filtration, the filtrate wasconcentrated to give tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (240mg, 78%), which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 8.26 (d, J=2.3 Hz, 1H), 8.09 (dd, J=8.8, 2.5 Hz, 1H), 7.79(t, J=5.9 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 1.48(s, 18H); HPLC ret. time 3.72 min, 10-100% CH₃CN, 5 min gradient.

E-4; tert-Butyl 2-tert-butyl-5-aminobenzylcarbamate

To a solution of tert-butyl 2-tert-butyl-5-nitrobenzylcarbamate (20 mg,0.065 mmol) in 5% AcOH-MeOH (1 mL) was added 10% Pd—C (14 mg) undernitrogen atmosphere. The mixture was stirred under H₂ (1 atm) at roomtemperature for 1 h. The catalyst was removed via filtration throughCelite, and the filtrate was concentrated to give tert-butyl2-tert-butyl-5-aminobenzylcarbamate (E-4), which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J=8.5 Hz, 1H),6.62 (d, J=2.6 Hz, 1H), 6.47 (dd, J=8.5, 2.6 Hz, 1H), 4.61 (br s, 1H),4.40 (d, J=5.1 Hz, 2H), 4.15 (br s, 2H), 1.39 (s, 9H), 1.29 (s, 9H);HPLC ret. time 2.47 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 279.3 m/z(MH⁺).

Example 4

2-tert-Butyl-5-nitrobenzoic acid

A solution of 2-tert-butyl-5-nitrobenzonitrile (204 mg, 1 mmol) in 5 mLof 75% H₂SO₄ was microwaved at 200° C. for 30 min. The reaction mixturewas poured into ice, extracted with EtOAc, washed with brine and driedover MgSO₄. After filtration, the filtrate was concentrated to give2-tert-butyl-5-nitrobenzoic acid (200 mg, 90%), which was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (d, J=2.6 Hz, 1H),8.24 (dd, J=8.9, 2.6 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H) 1.51 (s, 9H); HPLCret. time 2.97 min, 10-100% CH₃CN, 5 min gradient.

Methyl 2-tert-butyl-5-nitrobenzoate

To a mixture of 2-tert-butyl-5-nitrobenzoic acid (120 mg, 0.53 mmol) andK₂CO₃ (147 mg, 1.1 mmol) in DMF (5.0 mL) was added CH₃I (40 μL, 0.64mmol). The reaction mixture was stirred at room temperature for 10 min,diluted with water and extracted with EtOAc. The combined organic layerswere washed with brine and dried over MgSO₄. After filtration, thefiltrate was concentrated to give methyl 2-tert-butyl-5-nitrobenzoate,which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ8.20 (d, J=2.6 Hz, 1H), 8.17 (t, J=1.8 Hz, 1H), 7.66 (d, J=8.6 Hz, 1H),4.11 (s, 3H), 1.43 (s, 9H).

E-6; Methyl 2-tert-butyl-5-aminobenzoate

To a refluxing solution of 2-tert-butyl-5-nitrobenzoate (90 mg, 0.38mmol) in EtOH (2.0 mL) was added potassium formate (400 mg, 4.76 mmol)in water (1 mL), followed by the addition of 20 mg of 10% Pd—C. Thereaction mixture was refluxed for additional 40 min, cooled to roomtemperature and filtered through Celite. The filtrate was concentratedto give methyl 2-tert-butyl-5-aminobenzoate (E-6) (76 mg, 95%), whichwas used without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.24(d, J=8.6 Hz, 1H), 6.67 (dd, J=8.6, 2.7 Hz, 1H), 6.60 (d, J=2.7 Hz, 1H),3.86 (s, 3H), 1.34 (s, 9H); HPLC ret. time 2.19 min, 10-99% CH₃CN, 5 minrun; ESI-MS 208.2 m/z (MH⁺).

Example 5

2-tert-Butyl-5-nitrobenzene-1-sulfonyl chloride

A suspension of 2-tert-butyl-5-nitrobenzenamine (0.971 g, 5 mmol) inconc. HCl (5 mL) was cooled to 5-10° C. and a solution of NaNO₂ (0.433g, 6.3 mmol) in H₂O (0.83 mL) was added dropwise. Stirring was continuedfor 0.5 h, after which the mixture was vacuum filtered. The filtrate wasadded, simultaneously with a solution of Na₂SO₃ (1.57 g, 12.4 mmol) inH₂O (2.7 mL), to a stirred solution of CuSO₄ (0.190 g, 0.76 mmol) andNa₂SO₃ (1.57 g, 12.4 mmol) in HCl (11.7 mL) and H₂O (2.7 mL) at 3-5° C.Stirring was continued for 0.5 h and the resulting precipitate wasfiltered off, washed with water and dried to give2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (0.235 g, 17%). ¹H NMR(400 MHz, DMSO-d₆) δ 9.13 (d, J=2.5 Hz, 1H), 8.36 (dd, J=8.9, 2.5 Hz,1H), 7.88 (d, J=8.9 Hz, 1H), 1.59 (s, 9H).

2-tert-Butyl-5-nitrobenzene-1-sulfonamide

To a solution of 2-tert-butyl-5-nitrobenzene-1-sulfonyl chloride (100mg, 0.36 mmol) in ether (2 mL) was added aqueous NH₄OH (128 μL, 3.6mmol) at 0° C. The mixture was stirred at room temperature overnight,diluted with water and extracted with ether. The combined ether extractswere washed with brine and dried over Na₂SO₄. After removal of solvent,the residue was purified by column chromatography (0-50% EtOAc-Hexane)to give 2-tert-butyl-5-nitrobenzene-1-sulfonamide (31.6 mg, 34%).

E-7; 2-tert-Butyl-5-aminobenzene-1-sulfonamide

A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamide (32 mg, 0.12mmol) and SnCl₂ 2H₂O (138 mg, 0.61 mmol) in EtOH (1.5 mL) was heated inmicrowave oven at 100° C. for 30 min. The mixture was diluted with EtOAcand water, basified with sat. NaHCO₃ and filtered through Celite. Theorganic layer was separated from water and dried over Na₂SO₄. Solventwas removed by evaporation to provide2-tert-butyl-5-aminobenzene-1-sulfonamide (E-7) (28 mg, 100%), which wasused without further purification. HPLC ret. time 1.99 min, 10-99%CH₃CN, 5 min run; ESI-MS 229.3 m/z (MH⁺).

Example 6

E-8; (2-tert-Butyl-5-aminophenyl)methanol

To a solution of methyl 2-tert-butyl-5-aminobenzoate (159 mg, 0.72 mmol)in THF (5 mL) was added dropwise LiAlH₄ (1.4 mL, 1M in THF, 1.4 mmol) at0° C. The reaction mixture was refluxed for 2 h, diluted with H₂O andextracted with EtOAc. The combined organic layers were washed with brineand dried over MgSO₄. After filtration, the filtrate was concentrated togive (2-tert-butyl-5-aminophenyl)methanol (E-8) (25 mg, 20%), which wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d,J=8.5 Hz, 1H), 6.87 (d, J=2.6 Hz, 1H), 6.56 (dd, J=8.4, 2.7 Hz, 1H),4.83 (s, 2H), 1.36 (s, 9H).

Example 7

1-Methyl-pyridinium Monomethyl Sulfuric Acid Salt

Methyl sulfate (30 mL, 39.8 g, 0.315 mol) was added dropwise to drypyridine (25.0 g, 0.316 mol) added dropwise. The mixture was stirred atroom temperature for 10 min, then at 100° C. for 2 h. The mixture wascooled to room temperature to give crude 1-methyl-pyridinium monomethylsulfuric acid salt (64.7 g, quant.), which was used without furtherpurification.

1-Methyl-2-pyridone

A solution of 1-methyl-pyridinium monomethyl sulfuric acid salt (50 g,0.243 mol) in water (54 mL) was cooled to 0° C. Separate solutions ofpotassium ferricyanide (160 g, 0.486 mol) in water (320 mL) and sodiumhydroxide (40 g, 1.000 mol) in water (67 mL) were prepared and addeddropwise from two separatory funnels to the well-stirred solution of1-methyl-pyridinium monomethyl sulfuric acid salt, at such a rate thatthe temperature of reaction mixture did not rise above 10° C. The rateof addition of these two solutions was regulated so that all the sodiumhydroxide solution had been introduced into the reaction mixture whenone-half of the potassium Ferric Cyanide solution had been added. Afteraddition was complete, the reaction mixture was allowed to warm to roomtemperature and stirred overnight. Dry sodium carbonate (91.6 g) wasadded, and the mixture was stirred for 10 min. The organic layer wasseparated, and the aqueous layer was extracted with CH₂Cl₂ (100 mL×3).The combined organic layers were dried and concentrated to yield1-methyl-2-pyridone (25.0 g, 94%), which was used without furtherpurification.

1-Methyl-3,5-dinitro-2-pyridone

1-Methyl-2-pyridone (25.0 g, 0.229 mol) was added to sulfuric acid (500mL) at 0° C. After stirring for 5 min., nitric acid (200 mL) was addeddropwise at 0° C. After addition, the reaction temperature was slowlyraised to 100° C., and then maintained for 5 h. The reaction mixture waspoured into ice, basified with potassium carbonate to pH 8 and extractedwith CH₂Cl₂ (100 mL×3). The combined organic layers were dried overNa₂SO₄ and concentrated to yield 1-methyl-3,5-dinitro-2-pyridone (12.5g, 28%), which was used without further purification.

2-Isopropyl-5-nitro-pyridine

To a solution of 1-methyl-3,5-dinitro-2-pyridone (8.0 g, 40 mmol) inmethyl alcohol (20 mL) was added dropwise 3-methyl-2-butanone (5.1 mL,48 mmol), followed by ammonia solution in methyl alcohol (10.0 g, 17%,100 mmol). The reaction mixture was heated at 70° C. for 2.5 h underatmospheric pressure. The solvent was removed under vacuum and theresidual oil was dissolved in CH₂Cl₂, and then filtered. The filtratewas dried over Na₂SO₄ and concentrated to afford2-isopropyl-5-nitro-pyridine (1.88 g, 28%).

E-9; 2-Isopropyl-5-amino-pyridine

2-Isopropyl-5-nitro-pyridine (1.30 g, 7.82 mmol) was dissolved in methylalcohol (20 mL), and Raney Ni (0.25 g) was added. The mixture wasstirred under H₂ (1 atm) at room temperature for 2 h. The catalyst wasfiltered off, and the filtrate was concentrated under vacuum to give2-isopropyl-5-amino-pyridine (E-9) (0.55 g, 52%). ¹H NMR (CDCl₃) δ 8.05(s, 1H), 6.93-6.99 (m, 2H), 3.47 (br s, 2H), 2.92-3.02 (m, 1H),1.24-1.26 (m, 6H). ESI-MS 137.2 m/z (MH⁺).

Example 8

Phosphoric acid 2,4-di-tert-butyl-phenyl ester diethyl ester

To a suspension of NaH (60% in mineral oil, 6.99 g, 174.7 mmol) in THF(350 mL) was added dropwise a solution of 2,4-di-tert-butylphenol (35 g,169.6 mmol) in THF (150 mL) at 0° C. The mixture was stirred at 0° C.for 15 min and then phosphorochloridic acid diethyl ester (30.15 g,174.7 mmol) was added dropwise at 0° C. After addition, the mixture wasstirred at this temperature for 15 min. The reaction was quenched withsat. NH₄Cl (300 mL). The organic layer was separated and the aqueousphase was extracted with Et₂O (350 mL×2). The combined organic layerswere washed with brine, dried over anhydrous Na₂SO₄ and concentratedunder vacuum to give crude phosphoric acid 2,4-di-tert-butyl-phenylester diethyl ester as a yellow oil (51 g, contaminated with somemineral oil), which was used directly in the next step.

1,3-Di-tert-butyl-benzene

To NH₃ (liquid, 250 mL) was added a solution of phosphoric acid2,4-di-tert-butyl-phenyl ester diethyl ester (51 g, crude from laststep, about 0.2 mol) in Et₂O (anhydrous, 150 mL) at −78° C. under N₂atmosphere. Lithium metal was added to the solution in small piecesuntil a blue color persisted. The reaction mixture was stirred at −78°C. for 15 min and then quenched with sat. NH₄Cl solution until themixture turned colorless. Liquid NH₃ was evaporated and the residue wasdissolved in water, extracted with Et₂O (300 mL×2). The combined organicphases were dried over Na₂SO₄ and concentrated to give crude1,3-di-tert-butyl-benzene as a yellow oil (30.4 g, 94% over 2 steps,contaminated with some mineral oil), which was used directly in nextstep.

2,4-Di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde

To a stirred solution of 1,3-di-tert-butyl-benzene (30 g, 157.6 mmol) indry CH₂Cl₂ (700 mL) was added TiCl₄ (37.5 g, 197 mmol) at 0° C., andfollowed by dropwise addition of MeOCHCl₂ (27.3 g, 236.4 mmol). Thereaction was allowed to warm to room temperature and stirred for 1 h.The mixture was poured into ice-water and extracted with CH₂Cl₂. Thecombined organic phases were washed with NaHCO₃ and brine, dried overNa₂SO₄ and concentrated. The residue was purified by columnchromatography (petroleum ether) to give a mixture of2,4-di-tert-butyl-benzaldehyde and 3,5-di-tert-butyl-benzaldehyde (21 g,61%).

2,4-Di-tert-butyl-5-nitro-benzaldehyde and3,5-di-tert-butyl-2-nitro-benzaldehyde

To a mixture of 2,4-di-tert-butyl-benzaldehyde and3,5-di-tert-butyl-benzaldehyde in H₂SO₄ (250 mL) was added KNO₃ (7.64 g,75.6 mmol) in portions at 0° C. The reaction mixture was stirred at thistemperature for 20 min and then poured into crushed ice. The mixture wasbasified with NaOH solution to pH 8 and extracted with Et₂O (10 mL×3).The combined organic layers were washed with water and brine andconcentrated. The residue was purified by column chromatography(petroleum ether) to give a mixture of2,4-di-tert-butyl-5-nitro-benzaldehyde and3,5-di-tert-butyl-2-nitro-benzaldehyde (2:1 by NMR) as a yellow solid(14.7 g, 82%). After further purification by column chromatography(petroleum ether), 2,4-di-tert-butyl-5-nitro-benzaldehyde (2.5 g,contains 10% 3,5-di-tert-butyl-2-nitro-benzaldehyde) was isolated.

1,5-Di-tert-butyl-2-difluoromethyl-4-nitro-benzene and1,5-Di-tert-butyl-3-difluoromethyl-2-nitro-benzene

2,4-Di-tert-butyl-5-nitro-benzaldehyde (2.4 g, 9.11 mmol, contaminatedwith 10% 3,5-di-tert-butyl-2-nitro-benzaldehyde) in neat deoxofluorsolution was stirred at room temperature for 5 h. The reaction mixturewas poured into cooled sat. NaHCO₃ solution and extracted withdichloromethane. The combined organics were dried over Na₂SO₄,concentrated and purified by column chromatography (petroleum ether) togive 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene (1.5 g) and amixture of 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene and1,5-di-tert-butyl-3-difluoromethyl-2-nitro-benzene (0.75 g, contains 28%1,5-di-tert-butyl-3-difluoromethyl-2-nitro-benzene).

E-10; 1,5-Di-tert-butyl-2-difluoromethyl-4-amino-benzene

To a suspension of iron powder (5.1 g, 91.1 mmol) in 50% acetic acid (25ml) was added 1,5-di-tert-butyl-2-difluoromethyl-4-nitro-benzene (1.3 g,4.56 mmol). The reaction mixture was heated at 115° C. for 15 min. Solidwas filtered off was washed with acetic acid and CH₂Cl₂. The combinedfiltrate was concentrated and treated with HCl/MeOH. The precipitate wascollected via filtration, washed with MeOH and dried to give1,5-Di-tert-butyl-2-difluoromethyl-4-amino-benzene HCl salt (E-10) as awhite solid (1.20 g, 90%). ¹H NMR (DMSO-d₆) δ 7.35-7.70 (t, J=53.7 Hz,1H), 7.56 (s, 1H), 7.41 (s, 1H), 1.33-1.36 (d, J=8.1 Hz, 1H); ESI-MS256.3 m/z (MH⁺).

Example 9 General Scheme

Method A

In a 2-dram vial, 2-bromoaniline (100 mg, 0.58 mmol) and thecorresponding aryl boronic acid (0.82 mmol) were dissolved in THF (1mL). H₂O (500 μL) was added followed by K₂CO₃ (200 mg, 1.0 mmol) andPd(PPh₃)₄ (100 mg, 0.1 mmol). The vial was purged with argon and sealed.The vial was then heated at 75° C. for 18 h. The crude sample wasdiluted in EtOAc and filtered through a silica gel plug. The organicswere concentrated via Savant Speed-vac. The crude amine was used withoutfurther purification.

Method B

In a 2-dram vial, the corresponding aryl boronic acid (0.58 mmol) wasadded followed by KF (110 mg, 1.9 mmol). The solids were suspended inTHF (2 mL), and then 2-bromoaniline (70 μL, 0.58 mmol) was added. Thevial was purged with argon for 1 min. P(^(t)Bu)₃ (100 μL, 10% sol. inhexanes) was added followed by Pd₂(dba)₃ (900 μL, 0.005 M in THF). Thevial was purged again with argon and sealed. The vial was agitated on anorbital shaker at room temperature for 30 min and heated in a heatingblock at 80° C. for 16 h. The vial was then cooled to 20° C. and thesuspension was passed through a pad of Celite. The pad was washed withEtOAc (5 mL). The organics were combined and concentrated under vacuumto give a crude amine that was used without further purification.

The table below includes the amines made following the general schemeabove.

Product Name Method F-1 4′-Methyl-biphenyl-2-ylamine A F-23′-Methyl-biphenyl-2-ylamine A F-3 2′-Methyl-biphenyl-2-ylamine A F-42′,3′-Dimethyl-biphenyl-2-ylamine A F-5(2′-Amino-biphenyl-4-yl)-methanol A F-6N*4′*,N*4′*-Dimethyl-biphenyl-2,4′-diamine B F-72′-Trifluoromethyl-biphenyl-2-ylamine B F-8(2′-Amino-biphenyl-4-yl)-acetonitrile A F-94′-Isobutyl-biphenyl-2-ylamine A F-103′-Trifluoromethyl-biphenyl-2-ylamine B F-11 2-Pyridin-4-yl-phenylamineB F-12 2-(1H-Indol-5-yl)-phenylamine B F-133′,4′-Dimethyl-biphenyl-2-ylamine A F-14 4′-Isopropyl-biphenyl-2-ylamineA F-15 3′-Isopropyl-biphenyl-2-ylamine A F-164′-Trifluoromethyl-biphenyl-2-ylamine B F-174′-Methoxy-biphenyl-2-ylamine B F-18 3′-Methoxy-biphenyl-2-ylamine BF-19 2-Benzo[1,3]dioxol-5-yl-phenylamine B F-203′-Ethoxy-biphenyl-2-ylamine B F-21 4′-Ethoxy-biphenyl-2-ylamine B F-222′-Ethoxy-biphenyl-2-ylamine B F-23 4′-Methylsulfanyl-biphenyl-2-ylamineB F-24 3′,4′-Dimethoxy-biphenyl-2-ylamine B F-252′,6′-Dimethoxy-biphenyl-2-ylamine B F-262′,5′-Dimethoxy-biphenyl-2-ylamine B F-272′,4′-Dimethoxy-biphenyl-2-ylamine B F-285′-Chloro-2′-methoxy-biphenyl-2-ylamine B F-294′-Trifluoromethoxy-biphenyl-2-ylamine B F-303′-Trifluoromethoxy-biphenyl-2-ylamine B F-314′-Phenoxy-biphenyl-2-ylamine B F-322′-Fluoro-3′-methoxy-biphenyl-2-ylamine B F-332′-Phenoxy-biphenyl-2-ylamine B F-342-(2,4-Dimethoxy-pyrimidin-5-yl)-phenylamine B F-355′-Isopropyl-2′-methoxy-biphenyl-2-ylamine B F-362′-Trifluoromethoxy-biphenyl-2-ylamine B F-374′-Fluoro-biphenyl-2-ylamine B F-38 3′-Fluoro-biphenyl-2-ylamine B F-392′-Fluoro-biphenyl-2-ylamine B F-40 2′-Amino-biphenyl-3-carbonitrile BF-41 4′-Fluoro-3′-methyl-biphenyl-2-ylamine B F-424′-Chloro-biphenyl-2-ylamine B F-43 3′-Chloro-biphenyl-2-ylamine B F-443′,5′-Difluoro-biphenyl-2-ylamine B F-452′,3′-Difluoro-biphenyl-2-ylamine B F-463′,4′-Difluoro-biphenyl-2-ylamine B F-472′,4′-Difluoro-biphenyl-2-ylamine B F-482′,5′-Difluoro-biphenyl-2-ylamine B F-493′-Chloro-4′-fluoro-biphenyl-2-ylamine B F-503′,5′-Dichloro-biphenyl-2-ylamine B F-512′,5′-Dichloro-biphenyl-2-ylamine B F-522′,3′-Dichloro-biphenyl-2-ylamine B F-533′,4′-Dichloro-biphenyl-2-ylamine B F-54 2′-Amino-biphenyl-4-carboxylicacid methyl ester B F-55 2′-Amino-biphenyl-3-carboxylic acid methylester B F-56 2′-Methylsulfanyl-biphenyl-2-ylamine B F-57N-(2′-Amino-biphenyl-3-yl)-acetamide B F-584′-Methanesulfinyl-biphenyl-2-ylamine B F-592′,4′-Dichloro-biphenyl-2-ylamine B F-604′-Methanesulfonyl-biphenyl-2-ylamine B F-612′-Amino-biphenyl-2-carboxylic acid isopropyl ester B F-622-Furan-2-yl-phenylamine B F-631-[5-(2-Amino-phenyl)-thiophen-2-yl]-ethanone B F-642-Benzo[b]thiophen-2-yl-phenylamine B F-652-Benzo[b]thiophen-3-yl-phenylamine B F-66 2-Furan-3-yl-phenylamine BF-67 2-(4-Methyl-thiophen-2-yl)-phenylamine B F-685-(2-Amino-phenyl)-thiophene-2-carbonitrile B

Example 10

Ethyl 2-(4-nitrophenyl)-2-methylpropanoate

Sodium t-butoxide (466 mg, 4.85 mmol) was added to DMF (20 mL) at 0° C.The cloudy solution was re-cooled to 5° C. Ethyl 4-nitrophenylacetate(1.0 g, 4.78 mmol) was added. The purple slurry was cooled to 5° C. andmethyl iodide (0.688 mL, 4.85 mmol) was added over 40 min. The mixturewas stirred at 5-10° C. for 20 min, and then re-charged with sodiumt-butoxide (466 mg, 4.85 mmol) and methyl iodide (0.699 mL, 4.85 mmol).The mixture was stirred at 5-10° C. for 20 min and a third charge ofsodium t-butoxide (47 mg, 0.48 mmol) was added followed by methyl iodide(0.057 mL, 0.9 mmol). Ethyl acetate (100 mL) and HCl (0.1 N, 50 mL) wereadded. The organic layer was separated, washed with brine and dried overNa₂SO₄. After filtration, the filtrate was concentrated to provide ethyl2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 80%), which was usedwithout further purification.

G-1; Ethyl 2-(4-aminophenyl)-2-methylpropanoate

A solution of ethyl 2-(4-nitrophenyl)-2-methylpropanoate (900 mg, 3.8mmol) in EtOH (10 mL) was treated with 10% Pd—C (80 mg) and heated to45° C. A solution of potassium formate (4.10 g, 48.8 mmol) in H₂O (11mL) was added over a period of 15 min. The reaction mixture was stirredat 65° C. for 2 h and then treated with additional 300 mg of Pd/C. Thereaction was stirred for 1.5 h and then filtered through Celite. Thesolvent volume was reduced by approximately 50% under reduced pressureand extracted with EtOAc. The organic layers were dried over Na₂SO₄ andthe solvent was removed under reduced pressure to yield ethyl2-(4-aminophenyl)-2-methylpropanoate (G-1) (670 mg, 85%). ¹H NMR (400MHz, CDCl₃) δ 7.14 (d, J=8.5 Hz, 2H), 6.65 (d, J=8.6 Hz, 2H), 4.10 (q,J=7.1 Hz, 2H), 1.53 (s, 6H), 1.18 (t, J=7.1 Hz, 3H).

Example 11

G-2; 2-(4-Aminophenyl)-2-methylpropan-1-ol

A solution of ethyl 2-(4-aminophenyl)-2-methylpropanoate (30 mg, 0.145mmol) in THF (1 mL) was treated with LiAlH₄ (1M solution in THF, 0.226mL, 0.226 mmol) at 0° C. and stirred for 15 min. The reaction wastreated with 0.1N NaOH, extracted with EtOAc and the organic layers weredried over Na₂SO₄. The solvent was removed under reduced pressure toyield 2-(4-aminophenyl)-2-methylpropan-1-ol (G-2), which was usedwithoutfurther purification: ¹H NMR (400 MHz, CDCl₃) δ 7.17 (d, J=8.5Hz, 2H), 6.67 (d, J=8.5 Hz, 2H), 3.53 (s, 2H), 1.28 (s, 6H).

Example 12

2-methyl-2-(4-nitrophenyl)propanenitrile

A suspension of sodium tert-butoxide (662 mg, 6.47 mmol) in DMF (20 mL)at 0° C. was treated with 4-nitrophenylacetonitrile (1000 mg, 6.18 mmol)and stirred for 10 min. Methyl iodide (400 μL, 6.47 mmol) was addeddropwise over 15 min. The solution was stirred at 0-10° C. for 15 minand then at room temperature for additional 15 min. To this purplesolution was added sodium tert-butoxide (662 mg, 6.47 mmol) and thesolution was stirred for 15 min. Methyl iodide (400 μL, 6.47 mmol) wasadded dropwise over 15 min and the solution was stirred overnight.Sodium tert-butoxide (192 mg, 1.94 mmol) was added and the reaction wasstirred at 0° C. for 10 minutes. Methyl iodide (186 μL, 2.98 mmol) wasadded and the reaction was stirred for Ih. The reaction mixture was thenpartitioned between 1N HCl (50 mL) and EtOAc (75 mL). The organic layerwas washed with 1 N HCl and brine, dried over Na₂SO₄ and concentrated toyield 2-methyl-2-(4-nitrophenyl)propanenitrile as a green waxy solid(1.25 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ 8.24 (d, J=8.9 Hz, 2H), 7.66(d, J=8.9 Hz, 2H), 1.77 (s, 6H).

2-Methyl-2-(4-nitrophenyl)propan-1-amine

To a cooled solution of 2-methyl-2-(4-nitrophenyl)propanenitrile (670mg, 3.5 mmol) in THF (15 mL) was added BH₃ (1M in THF, 14 mL, 14 mmol)dropwise at 0° C. The mixture was warmed to room temperature and heatedat 70° C. for 2 h. 1N HCl solution (2 mL) was added, followed by theaddition of NaOH until pH>7. The mixture was extracted with ether andether extract was concentrated to give2-methyl-2-(4-nitrophenyl)propan-1-amine (610 mg, 90%), which was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 8.20 (d, J=9.0Hz, 2H), 7.54 (d, J=9.0 Hz, 2H), 2.89 (s, 2H), 1.38 (s, 6H).

tert-Butyl 2-methyl-2-(4-nitrophenyl)propylcarbamate

To a cooled solution of 2-methyl-2-(4-nitrophenyl)propan-1-amine (600mg, 3.1 mmol) and 1N NaOH (3 mL, 3 mmol) in 1,4-dioxane (6 mL) and water(3 mL) was added Boc₂O (742 mg, 3.4 mmol) at 0° C. The reaction wasallowed to warm to room temperature and stirred overnight. The reactionwas made acidic with 5% KHSO₄ solution and then extracted with ethylacetate. The organic layer was dried over MgSO₄ and concentrated to givetert-butyl 2-methyl-2-(4-nitrophenyl)propylcarbamate (725 mg, 80%),which was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ8.11 (d, J=8.9 Hz, 2H), 7.46 (d, J=8.8 Hz, 2H), 3.63 (s, 2H), 1.31-1.29(m, 15H).

G-3; tert-Butyl 2-methyl-2-(4-aminophenyl)propylcarbamate

To a refluxing solution of tert-butyl2-methyl-2-(4-nitrophenyl)propylcarbamate (725 mg, 2.5 mmol) andammonium formate (700 mg, 10.9 mmol) in EtOH (25 mL) was added Pd-5% wton carbon (400 mg). The mixture was refluxed for 1 h, cooled andfiltered through Celite. The filtrate was concentrated to givetert-butyl 2-methyl-2-(4-aminophenyl)propylcarbamate (G-3) (550 mg,83%), which was used without further purification. ¹H NMR (400 MHz,DMSO-d₆) δ 6.99 (d, J=8.5 Hz, 2H), 6.49 (d, J=8.6 Hz, 2H), 4.85 (s, 2H),3.01 (d, J=6.3 Hz, 2H), 1.36 (s, 9H), 1.12 (s, 6H); HPLC ret. time 2.02min, 10-99% CH₃CN, 5 min run; ESI-MS 265.2 m/z (MH⁺).

Example 13

7-Nitro-1,2,3,4-tetrahydro-naphthalen-1-ol

7-Nitro-3,4-dihydro-2H-naphthalen-1-one (200 mg, 1.05 mmol) wasdissolved in methanol (5 mL) and NaBH₄ ((78 mg, 2.05 mmol) was added inportions. The reaction was stirred at room temperature for 20 min andthen concentrated and purified by column chromatography (10-50% ethylacetate-hexanes) to yield 7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol(163 mg, 80%). ¹H NMR (400 MHz, CD₃CN) δ 8.30 (d, J=2.3 Hz, 1H), 8.02(dd, J=8.5, 2.5 Hz, 1H), 7.33 (d, J=8.5 Hz, 1H), 4.76 (t, J=5.5 Hz, 1H),2.96-2.80 (m, 2H), 2.10-1.99 (m, 2H), 1.86-1.77 (m, 2H); HPLC ret. time2.32 min, 10-99% CH₃CN, 5 min run.

H-1; 7-Amino-1,2,3,4-tetrahydro-naphthalen-1-ol

7-nitro-1,2,3,4-tetrahydro-naphthalen-1-ol (142 mg, 0.73 mmol) wasdissolved in methanol (10 mL) and the flask was flushed with N₂ (g). 10%Pd—C (10 mg) was added and the reaction was stirred under H₂ (1 atm) atroom temperature overnight. The reaction was filtered and the filtrateconcentrated to yield 7-amino-1,2,3,4-tetrahydro-naphthalen-1-ol (H-1)(113 mg, 95%). HPLC ret. time 0.58 min, 10-99% CH₃CN, 5 min run; ESI-MS164.5 m/z (MH⁺).

Example 14

7-Nitro-3,4-dihydro-2H-naphthalen-1-one oxime

To a solution of 7-nitro-3,4-dihydro-2H-naphthalen-1-one (500 mg, 2.62mmol) in pyridine (2 mL) was added hydroxylamine solution (1 mL, 50%solution in water). The reaction was stirred at room temperature for 1h, then concentrated and purified by column chromatography (10-50% ethylacetate-hexanes) to yield 7-nitro-3,4-dihydro-2H-naphthalen-1-one oxime(471 mg, 88%). HPLC ret. time 2.67 min, 10-99% CH₃CN, 5 min run; ESI-MS207.1 m/z (MH⁺).

1,2,3,4-Tetrahydro-naphthalene-1,7-diamine

7-Nitro-3,4-dihydro-2H-naphthalen-1-one oxime (274 mg, 1.33 mmol) wasdissolved in methanol (10 mL) and the flask was flushed with N₂ (g). 10%Pd—C (50 mg) was added and the reaction was stirred under H₂ (1 atm) atroom temperature overnight. The reaction was filtered and the filtratewas concentrated to yield 1,2,3,4-tetrahydro-naphthalene-1,7-diamine(207 mg, 96%). ¹H NMR (400 MHz, DMSO-d₆) δ 6.61-6.57 (m, 2H), 6.28 (dd,J=8.0, 2.4 Hz, 1H), 4.62 (s, 2H), 3.58 (m, 1H), 2.48-2.44 (m, 2H),1.78-1.70 (m, 2H), 1.53-1.37 (m, 2H).

H-2; (7-Amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acidtert-butyl ester

To a solution of 1,2,3,4-tetrahydro-naphthalene-1,7-diamine (154 mg,0.95 mmol) and triethylamine (139 μL, 1.0 mmol) in methanol (2 mL)cooled to 0° C. was added di-tert-butyl dicarbonate (207 mg, 0.95 mmol).The reaction was stirred at 0° C. and then concentrated and purified bycolumn chromatography (5-50% methanol-dichloromethane) to yield(7-amino-1,2,3,4-tetrahydro-naphthalen-1-yl)-carbamic acid tert-butylester (H-2) (327 mg, quant.). HPLC ret. time 1.95 min, 10-99% CH₃CN, 5min run; ESI-MS 263.1 m/z (MH⁺).

Example 15

N-(2-Bromo-benzyl)-2,2,2-trifluoro-acetamide

To a solution of 2-bromobenzylamine (1.3 mL, 10.8 mmol) in methanol (5mL) was added ethyl trifluoroacetate (1.54 mL, 21.6 mmol) andtriethylamine (1.4 mL, 10.8 mmol) under a nitrogen atmosphere. Thereaction was stirred at room temperature for 1 h. The reaction mixturewas then concentrated under vacuum to yieldN-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (3.15 g, quant.). HPLC ret.time 2.86 min, 10-99% CH₃CN, 5 min run; ESI-MS 283.9 m/z (MH⁺).

I-1; N-(4′-Amino-biphenyl-2-ylmethyl)-2,2,2-trifluoro-acetamide

A mixture of N-(2-bromo-benzyl)-2,2,2-trifluoro-acetamide (282 mg, 1.0mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (284 mg,1.3 mmol), Pd(OAc)₂ (20 mg, 0.09 mmol) and PS—PPh₃ (40 mg, 3 mmol/g,0.12 mmol) was dissolved in DMF (5 mL) and 4M K₂CO₃ solution (0.5 mL)was added. The reaction was heated at 80° C. overnight. The mixture wasfiltered, concentrated and purified by column chromatography (0-50%ethyl acetate-hexanes) to yieldN-(4′-amino-biphenyl-2-ylmethyl)-2,2,2-trifluoro-acetamide (1-1) (143mg, 49%). HPLC ret. time 1.90 min, 10-99% CH₃CN, 5 min run; ESI-MS 295.5m/z (MH⁺).

Commercially Available Amines

Amine Name J-1 2-methoxy-5-methylbenzenamine J-22,6-diisopropylbenzenamine J-3 pyridin-2-amine J-4 4-pentylbenzenamineJ-5 isoquinolin-3-amine J-6 aniline J-7 4-phenoxybenzenamine J-82-(2,3-dimethylphenoxy)pyridin-3-amine J-9 4-ethynylbenzenamine J-102-sec-butylbenzenamine J-11 2-amino-4,5-dimethoxybenzonitrile J-122-tert-butylbenzenamine J-131-(7-amino-3,4-dihydroisoquinolin-2(1H)-yl)ethanone J-144-(4-methyl-4H-1,2,4-triazol-3-yl)benzenamine J-152′-Aminomethyl-biphenyl-4-ylamine J-16 1H-Indazol-6-ylamine J-172-(2-methoxyphenoxy)-5-(trifluoromethyl)benzenamine J-182-tert-butylbenzenamine J-19 2,4,6-trimethylbenzenamine J-205,6-dimethyl-1H-benzo[d]imidazol-2-amine J-212,3-dihydro-1H-inden-4-amine J-22 2-sec-butyl-6-ethylbenzenamine J-23quinolin-5-amine J-24 4-(benzyloxy)benzenamine J-252′-Methoxy-biphenyl-2-ylamine J-26 benzo[c][1,2,5]thiadiazol-4-amineJ-27 3-benzylbenzenamine J-28 4-isopropylbenzenamine J-292-(phenylsulfonyl)benzenamine J-30 2-methoxybenzenamine J-314-amino-3-ethylbenzonitrile J-32 4-methylpyridin-2-amine J-334-chlorobenzenamine J-34 2-(benzyloxy)benzenamine J-352-amino-6-chlorobenzonitrile J-36 3-methylpyridin-2-amine J-374-aminobenzonitrile J-38 3-chloro-2,6-diethylbenzenamine J-393-phenoxybenzenamine J-40 2-benzylbenzenamine J-412-(2-fluorophenoxy)pyridin-3-amine J-42 5-chloropyridin-2-amine J-432-(trifluoromethyl)benzenamine J-44(4-(2-aminophenyl)piperazin-1-yl)(phenyl)methanone J-451H-benzo[d][1,2,3]triazol-5-amine J-46 2-(1H-indol-2-yl)benzenamine J-474-Methyl-biphenyl-3-ylamine J-48 pyridin-3-amine J-493,4-dimethoxybenzenamine J-50 3H-benzo[d]imidazol-5-amine J-513-aminobenzonitrile J-52 6-chloropyridin-3-amine J-53 o-toluidine J-541H-indol-5-amine J-55 [1,2,4]triazolo[1,5-a]pyridin-8-amine J-562-methoxypyridin-3-amine J-57 2-butoxybenzenamine J-582,6-dimethylbenzenamine J-59 2-(methylthio)benzenamine J-602-(5-methylfuran-2-yl)benzenamine J-613-(4-aminophenyl)-3-ethylpiperidine-2,6-dione J-622,4-dimethylbenzenamine J-63 5-fluoropyridin-2-amine J-644-cyclohexylbenzenamine J-65 4-Amino-benzenesulfonamide J-662-ethylbenzenamine J-67 4-fluoro-3-methylbenzenamine J-682,6-dimethoxypyridin-3-amine J-69 4-tert-butylbenzenamine J-704-sec-butylbenzenamine J-71 5,6,7,8-tetrahydronaphthalen-2-amine J-723-(Pyrrolidine-1-sulfonyl)-phenylamine J-73 4-Adamantan-1-yl-phenylamineJ-74 3-amino-5,6,7,8-tetrahydronaphthalen-2-ol J-75benzo[d][1,3]dioxol-5-amine J-76 5-chloro-2-phenoxybenzenamine J-77N1-tosylbenzene-1,2-diamine J-78 3,4-dimethylbenzenamine J-792-(trifluoromethylthio)benzenamine J-80 1H-indol-7-amine J-813-methoxybenzenamine J-82 quinolin-8-amine J-832-(2,4-difluorophenoxy)pyridin-3-amine J-842-(4-aminophenyl)acetonitrile J-85 2,6-dichlorobenzenamine J-862,3-dihydrobenzofuran-5-amine J-87 p-toluidine J-882-methylquinolin-8-amine J-89 2-tert-butylbenzenamine J-903-chlorobenzenamine J-91 4-tert-butyl-2-chlorobenzenamine J-922-Amino-benzenesulfonamide J-93 1-(2-aminophenyl)ethanone J-94m-toluidine J-952-(3-chloro-5-(trifluoromethyl)pyridin-2-yloxy)benzenamine J-962-amino-6-methylbenzonitrile J-97 2-(prop-1-en-2-yl)benzenamine J-984-Amino-N-pyridin-2-yl-benzenesulfonamide J-99 2-ethoxybenzenamine J-100naphthalen-1-amine J-101 Biphenyl-2-ylamine J-1022-(trifluoromethyl)-4-isopropylbenzenamine J-103 2,6-diethylbenzenamineJ-104 5-(trifluoromethyl)pyridin-2-amine J-105 2-aminobenzamide J-1063-(trifluoromethoxy)benzenamine J-1073,5-bis(trifluoromethyl)benzenamine J-108 4-vinylbenzenamine J-1094-(trifluoromethyl)benzenamine J-110 2-morpholinobenzenamine J-1115-amino-1H-benzo[d]imidazol-2(3H)-one J-112 quinolin-2-amine J-1133-methyl-1H-indol-4-amine J-114 pyrazin-2-amine J-1151-(3-aminophenyl)ethanone J-116 2-ethyl-6-isopropylbenzenamine J-1172-(3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl)benzenamine J-118N-(4-amino-2,5-diethoxyphenyl)benzamide J-1195,6,7,8-tetrahydronaphthalen-1-amine J-1202-(1H-benzo[d]imidazol-2-yl)benzenamine J-1211,1-Dioxo-1H-1lambda*6*-benzo[b]thiophen-6-ylamine J-1222,5-diethoxybenzenamine J-123 2-isopropyl-6-methylbenzenamine J-124tert-butyl 5-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate J-1252-(2-aminophenyl)ethanol J-126 (4-aminophenyl)methanol J-1275-methylpyridin-2-amine J-128 2-(pyrrolidin-1-yl)benzenamine J-1294-propylbenzenamine J-130 3,4-dichlorobenzenamine J-1312-phenoxybenzenamine J-132 Biphenyl-2-ylamine J-133 2-chlorobenzenamineJ-134 2-amino-4-methylbenzonitrile J-135(2-aminophenyl)(phenyl)methanone J-136 aniline J-1373-(trifluoromethylthio)benzenamine J-1382-(2,5-dimethyl-1H-pyrrol-1-yl)benzenamine J-1394-(Morpholine-4-sulfonyl)-phenylamine J-1402-methylbenzo[d]thiazol-5-amine J-141 2-amino-3,5-dichlorobenzonitrileJ-142 2-fluoro-4-methylbenzenamine J-143 6-ethylpyridin-2-amine J-1442-(1H-pyrrol-1-yl)benzenamine J-145 2-methyl-1H-indol-5-amine J-146quinolin-6-amine J-147 1H-benzo[d]imidazol-2-amine J-1482-o-tolylbenzo[d]oxazol-5-amine J-149 5-phenylpyridin-2-amine J-150Biphenyl-2-ylamine J-151 4-(difluoromethoxy)benzenamine J-1525-tert-butyl-2-methoxybenzenamine J-1532-(2-tert-butylphenoxy)benzenamine J-154 3-aminobenzamide J-1554-morpholinobenzenamine J-156 6-aminobenzo[d]oxazol-2(3H)-one J-1572-phenyl-3H-benzo[d]imidazol-5-amine J-158 2,5-dichloropyridin-3-amineJ-159 2,5-dimethylbenzenamine J-160 4-(phenylthio)benzenamine J-1619H-fluoren-1-amine J-1622-(4-aminophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol J-1634-bromo-2-ethylbenzenamine J-164 4-methoxybenzenamine J-1653-(Piperidine-1-sulfonyl)-phenylamine J-166 quinoxalin-6-amine J-1676-(trifluoromethyl)pyridin-3-amine J-1683-(trifluoromethyl)-2-methylbenzenamine J-169(2-aminophenyl)(phenyl)methanol J-170 aniline J-1716-methoxypyridin-3-amine J-172 4-butylbenzenamine J-1733-(Morpholine-4-sulfonyl)-phenylamine J-174 2,3-dimethylbenzenamineJ-175 aniline J-176 Biphenyl-2-ylamine J-1772-(2,4-dichlorophenoxy)benzenamine J-178 pyridin-4-amine J-1792-(4-methoxyphenoxy)-5-(trifluoromethyl)benzenamine J-1806-methylpyridin-2-amine J-181 5-chloro-2-fluorobenzenamine J-1821H-indol-4-amine J-183 6-morpholinopyridin-3-amine J-184 aniline J-1851H-indazol-5-amine J-1862-[(Cyclohexyl-methyl-amino)-methyl]-phenylamine J-1872-phenylbenzo[d]oxazol-5-amine J-188 naphthalen-2-amine J-1892-aminobenzonitrile J-190 N1,N1-diethyl-3-methylbenzene-1,4-diamineJ-191 aniline J-192 2-butylbenzenamine J-193 1-(4-aminophenyl)ethanolJ-194 2-amino-4-methylbenzamide J-195 quinolin-3-amine J-1962-(piperidin-1-yl)benzenamine J-197 3-Amino-benzenesulfonamide J-1982-ethyl-6-methylbenzenamine J-199 Biphenyl-4-ylamine J-2002-(o-tolyloxy)benzenamine J-201 5-amino-3-methylbenzo[d]oxazol-2(3H)-oneJ-202 4-ethylbenzenamine J-203 2-isopropylbenzenamine J-2043-(trifluoromethyl)benzenamine J-205 2-amino-6-fluorobenzonitrile J-2062-(2-aminophenyl)acetonitrile J-207 2-(4-fluorophenoxy)pyridin-3-amineJ-208 aniline J-209 2-(4-methylpiperidin-1-yl)benzenamine J-2104-fluorobenzenamine J-211 2-propylbenzenamine J-2124-(trifluoromethoxy)benzenamine J-213 3-aminophenol J-2142,2-difluorobenzo[d][1,3]dioxol-5-amine J-2152,2,3,3-tetrafluoro-2,3-dihydrobenzo[b][1,4]dioxin-6-amine J-216N-(3-aminophenyl)acetamide J-2171-(3-aminophenyl)-3-methyl-1H-pyrazol-5(4H)-one J-2185-(trifluoromethyl)benzene-1,3-diamine J-2195-tert-butyl-2-methoxybenzene-1,3-diamine J-220N-(3-amino-4-ethoxyphenyl)acetamide J-221N-(3-Amino-phenyl)-methanesulfonamide J-222N-(3-aminophenyl)propionamide J-223 N1,N1-dimethylbenzene-1,3-diamineJ-224 N-(3-amino-4-methoxyphenyl)acetamide J-225 benzene-1,3-diamineJ-226 4-methylbenzene-1,3-diamine J-227 1H-indol-6-amine J-2286,7,8,9-tetrahydro-5H-carbazol-2-amine J-229 1H-indol-6-amine J-2301H-indol-6-amine J-231 1H-indol-6-amine J-232 1H-indol-6-amine J-2331H-indol-6-amine J-234 1H-indol-6-amine J-235 1H-indol-6-amine J-2361H-indol-6-amine J-237 1H-indol-6-amine J-238 1H-indol-6-amine J-2391-(6-Amino-2,3-dihydro-indol-1-yl)-ethanone J-2405-Chloro-benzene-1,3-diamine

Amides (Compounds of Formula I)

General Scheme:

a) Ar₁R7NH, coupling reagent, base, solvent. Examples of conditionsused: HATU, DIEA, DMF; BOP, DIEA, DMF; HBTU, Et₃N, CH₂Cl₂; PFP-TFA,pyridine

Specific Example

215; 4-Oxo-N-phenyl-1H-quinoline-3-carboxamide

To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (19 mg, 0.1mmol), HATU (38 mg, 0.1 mmol) and DIEA (34.9 μL, 0.2 mmol) in DMF (1 mL)was added aniline (18.2 μL, 0.2 mmol) and the reaction mixture wasstirred at room temperature for 3 h. The resulting solution was filteredand purified by HPLC (10-99% CH₃CN/H₂O) to yield4-oxo-N-phenyl-1H-quinoline-3-carboxamide (215) (12 mg, 45%). ¹H NMR(400 MHz, DMSO-d₆) δ 12.97 (s, 1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34(dd, J=8.1, 1.1 Hz, 1H), 7.83 (t, J=8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t,J=8.1H), 7.37 (t, J=7.9 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H); HPLC ret. time3.02 min, 10-99% CH₃CN, 5 min run; ESI-MS 265.1 m/z (MH⁺).

The table below lists other examples synthesized by the general schemeabove.

Compound of formula I Acid Amine  2 A-1 C-2  3 A-1 J-17  4 A-1 J-110  5A-1 G-2  6 A-1 E-8  7 A-1 J-118  8 A-1 D-7  9 A-1 J-197  11 A-1 F-7  12A-1 F-6  13 A-1 E-2  15 A-1 J-56  16 A-1 J-211  18 A-1 J-161  19 A-1J-112  20 A-1 J-200  21 A-1 J-98  23 A-1 C-15  24 A-1 J-72  25 A-1 F-57 26 A-1 J-196  29 A-21 J-208  31 A-1 J-87  32 A-1 B-21  33 A-1 J-227  34A-1 C-19  36 A-1 J-203  37 A-1 J-80  38 A-1 J-46  39 A-17 D-10  40 A-1J-125  42 A-1 J-95  43 A-1 C-16  44 A-1 J-140  45 A-1 J-205  47 A-1J-102  48 A-1 J-181  49 A-1 F-25  50 A-1 J-19  51 A-7 B-24  52 A-1 F-2 53 A-1 J-178  54 A-1 J-26  55 A-1 J-219  56 A-1 J-74  57 A-1 J-61  58A-1 D-4  59 A-1 F-35  60 A-1 D-11  61 A-1 J-174  62 A-1 J-106  63 A-1F-47  64 A-1 J-111  66 A-1 J-214  67 A-10 J-236  68 A-1 F-55  69 A-1 D-8 70 A-1 F-11  71 A-1 F-61  72 A-1 J-66  73 A-1 J-157  74 A-1 J-104  75A-1 J-195  76 A-1 F-46  77 A-1 B-20  78 A-1 J-92  79 A-1 F-41  80 A-1J-30  81 A-1 J-222  82 A-1 J-190  83 A-1 F-40  84 A-1 J-32  85 A-1 F-53 86 A-1 J-15  87 A-1 J-39  88 A-1 G-3  89 A-1 J-134  90 A-1 J-18  91 A-1J-38  92 A-1 C-13  93 A-1 F-68  95 A-1 J-189  96 A-1 B-9  97 A-1 F-34 99 A-1 J-4 100 A-1 J-182 102 A-1 J-117 103 A-2 C-9 104 A-1 B-4 106 A-1J-11 107 A-1 DC-6 108 A-1 DC-3 109 A-1 DC-4 110 A-1 J-84 111 A-1 J-43112 A-11 J-235 113 A-1 B-7 114 A-1 D-18 115 A-1 F-62 116 A-3 J-229 118A-1 F-12 120 A-1 J-1 121 A-1 J-130 122 A-1 J-49 123 A-1 F-66 124 A-2B-24 125 A-1 J-143 126 A-1 C-25 128 A-22 J-176 130 A-14 J-233 131 A-1J-240 132 A-1 J-220 134 A-1 F-58 135 A-1 F-19 136 A-1 C-8 137 A-6 C-9138 A-1 F-44 139 A-1 F-59 140 A-1 J-64 142 A-1 J-10 143 A-1 C-7 144 A-1J-213 145 A-1 B-18 146 A-1 J-55 147 A-1 J-207 150 A-1 J-162 151 A-1 F-67152 A-1 J-156 153 A-1 C-23 154 A-1 J-107 155 A-1 J-3 156 A-1 F-36 160A-1 D-6 161 A-1 C-3 162 A-1 J-171 164 A-1 J-204 165 A-1 J-65 166 A-1F-54 167 A-1 J-226 168 A-1 J-48 169 A-1 B-1 170 A-1 J-42 171 A-1 F-52172 A-1 F-64 173 A-1 J-180 174 A-1 F-63 175 A-1 DC-2 176 A-1 J-212 177A-1 J-57 178 A-1 J-153 179 A-1 J-154 180 A-1 J-198 181 A-1 F-1 182 A-1F-37 183 A-1 DC-1 184 A-15 J-231 185 A-1 J-173 186 A-1 B-15 187 A-1 B-3188 A-1 B-25 189 A-1 J-24 190 A-1 F-49 191 A-1 J-23 192 A-1 J-36 193 A-1J-68 194 A-1 J-37 195 A-1 J-127 197 A-1 J-167 198 A-1 J-210 199 A-1 F-3200 A-1 H-1 201 A-1 J-96 202 A-1 F-28 203 A-1 B-2 204 A-1 C-5 205 A-1J-179 206 A-1 J-8 207 A-1 B-17 208 A-1 C-12 209 A-1 J-126 210 A-17 J-101211 A-1 J-152 212 A-1 J-217 213 A-1 F-51 214 A-1 J-221 215 A-1 J-136 216A-1 J-147 217 A-1 J-185 218 A-2 C-13 219 A-1 J-114 220 A-1 C-26 222 A-1J-35 223 A-1 F-23 224 A-1 I-1 226 A-1 J-129 227 A-1 J-120 228 A-1 J-169229 A-1 J-59 230 A-1 J-145 231 A-1 C-17 233 A-1 J-239 234 A-1 B-22 235A-1 E-9 236 A-1 J-109 240 A-1 J-34 241 A-1 J-82 242 A-1 D-2 244 A-1J-228 245 A-1 J-177 246 A-1 J-78 247 A-1 F-33 250 A-1 J-224 252 A-1J-135 253 A-1 F-30 254 A-2 B-20 255 A-8 C-9 256 A-1 J-45 257 A-1 J-67259 A-1 B-14 261 A-1 F-13 262 A-1 DC-7 263 A-1 J-163 264 A-1 J-122 265A-1 J-40 266 A-1 C-14 267 A-1 J-7 268 A-1 E-7 270 A-1 B-5 271 A-1 D-9273 A-1 H-2 274 A-8 B-24 276 A-1 J-139 277 A-1 F-38 278 A-1 F-10 279 A-1F-56 280 A-1 J-146 281 A-1 J-62 283 A-1 F-18 284 A-1 J-16 285 A-1 F-45286 A-1 J-119 287 A-3 C-13 288 A-1 C-6 289 A-1 J-142 290 A-1 F-15 291A-1 C-10 292 A-1 J-76 293 A-1 J-144 294 A-1 J-54 295 A-1 J-128 296 A-17J-12 297 A-1 J-138 301 A-1 J-14 302 A-1 F-5 303 A-1 J-13 304 A-1 E-1 305A-1 F-17 306 A-1 F-20 307 A-1 F-43 308 A-1 J-206 309 A-1 J-5 310 A-1J-70 311 A-1 J-60 312 A-1 F-27 313 A-1 F-39 314 A-1 J-116 315 A-1 J-58317 A-1 J-85 319 A-2 C-7 320 A-1 B-6 321 A-1 J-44 322 A-1 J-22 324 A-1J-172 325 A-1 J-103 326 A-1 F-60 328 A-1 J-115 329 A-1 J-148 330 A-1J-133 331 A-1 J-105 332 A-1 J-9 333 A-1 F-8 334 A-1 DC-5 335 A-1 J-194336 A-1 J-192 337 A-1 C-24 338 A-1 J-113 339 A-1 B-8 344 A-1 F-22 345A-2 J-234 346 A-12 J-6 348 A-1 F-21 349 A-1 J-29 350 A-1 J-100 351 A-1B-23 352 A-1 B-10 353 A-1 D-10 354 A-1 J-186 355 A-1 J-25 357 A-1 B-13358 A-24 J-232 360 A-1 J-151 361 A-1 F-26 362 A-1 J-91 363 A-1 F-32 364A-1 J-88 365 A-1 J-93 366 A-1 F-16 367 A-1 F-50 368 A-1 D-5 369 A-1J-141 370 A-1 J-90 371 A-1 J-79 372 A-1 J-209 373 A-1 J-21 374 A-16J-238 375 A-1 J-71 376 A-1 J-187 377 A-5 J-237 378 A-1 D-3 380 A-1 J-99381 A-1 B-24 383 A-1 B-12 384 A-1 F-48 385 A-1 J-83 387 A-1 J-168 388A-1 F-29 389 A-1 J-27 391 A-1 F-9 392 A-1 J-52 394 A-22 J-170 395 A-1C-20 397 A-1 J-199 398 A-1 J-77 400 A-1 J-183 401 A-1 F-4 402 A-1 J-149403 A-1 C-22 405 A-1 J-33 406 A-6 B-24 407 A-3 C-7 408 A-1 J-81 410 A-1F-31 411 A-13 J-191 412 A-1 B-19 413 A-1 J-131 414 A-1 J-50 417 A-1 F-65418 A-1 J-223 419 A-1 J-216 420 A-1 G-1 421 A-1 C-18 422 A-1 J-20 423A-1 B-16 424 A-1 F-42 425 A-1 J-28 426 A-1 C-11 427 A-1 J-124 428 A-1C-1 429 A-1 J-218 430 A-1 J-123 431 A-1 J-225 432 A-1 F-14 433 A-1 C-9434 A-1 J-159 435 A-1 J-41 436 A-1 F-24 437 A-1 J-75 438 A-1 E-10 439A-1 J-164 440 A-1 J-215 441 A-1 D-19 442 A-1 J-165 443 A-1 J-166 444 A-1E-6 445 A-1 J-97 446 A-1 J-121 447 A-1 J-51 448 A-1 J-69 449 A-1 J-94450 A-1 J-193 451 A-1 J-31 452 A-1 J-108 453 A-1 D-1 454 A-1 J-47 455A-1 J-73 456 A-1 J-137 457 A-1 J-155 458 A-1 C-4 459 A-1 J-53 461 A-1J-150 463 A-1 J-202 464 A-3 C-9 465 A-1 E-4 466 A-1 J-2 467 A-1 J-86 468A-20 J-184 469 A-12 J-132 470 A-1 J-160 473 A-21 J-89 474 A-1 J-201 475A-1 J-158 477 A-1 J-63 478 A-1 B-11 479 A-4 J-230 480 A-23 J-175 481 A-1J-188 483 A-1 C-21 484 A-1 D-14 B-26-I A-1 B-26 B-27-I A-1 B-27 C-27-IA-1 C-27 D-12-I A-1 D-12 D-13-I A-1 D-13 D-15-I A-1 D-15 D-16-I A-1 D-16D-17-I A-1 D-17 DC-10-I A-1 DC-10 DC-8-I A-1 DC-8 DC-9-I A-1 DC-9

Indoles

Example 1 General Scheme

Specific Example

188-I; 6-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylicacid

A mixture of6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acidethyl ester (188) (450 mg, 1.2 mmol) and 1N NaOH solution (5 mL) in THF(10 mL) was heated at 85° C. overnight. The reaction mixture waspartitioned between EtOAc and water. The aqueous layer was acidifiedwith 1N HCl solution to pH 5, and the precipitate was filtered, washedwith water and air dried to yield6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid(188-I) (386 mg, 93%). ¹H-NMR (400 MHz, DMSO-d₆) δ 12.92-12.75 (m, 2H),11.33 (s, 1H), 8.84 (s, 1H), 8.71 (s, 1H), 8.30 (dd, J=8.1, 0.9 Hz, 1H),8.22 (s, 1H), 7.80-7.72 (m, 2H), 7.49 (t, J=8.0 Hz, 1H), 7.41 (t, J=2.7Hz, 1H), 6.51 (m, 1H); HPLC ret. time 2.95 min, 10-99% CH₃CN, 5 min run;ESI-MS 376.2 m/z (MH⁺).

343;N-[5-(Isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide

To a solution of6-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1H-indole-5-carboxylic acid(188-I) (26 mg, 0.08 mmol), HATU (38 mg, 0.1 mmol) and DIEA (35 μL, 0.2mmol) in DMF (1 mL) was added isobutylamine (7 mg, 0.1 mmol) and thereaction mixture was stirred at 65° C. overnight. The resulting solutionwas filtered and purified by HPLC (10-99% CH₃CN/H₂O) to yield theproduct,N-[5-(isobutylcarbamoyl)-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide(343) (20 mg, 66%). ¹H-NMR (400 MHz, DMSO-d₆) δ 12.66 (d, J=7.4 Hz, 1H),12.42 (s, 1H), 11.21 (s, 1H), 8.81 (d, J=6.6 Hz, 1H), 8.47 (s, 1H), 8.36(t, J=5.6 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 7.79 (t, J=7.9 Hz, 1H),7.72-7.71 (m, 2H), 7.51 (t, J=7.2 Hz, 1H), 7.38 (m, 1H), 6.48 (m, 1H),3.10 (t, J=6.2 Hz, 2H), 1.88 (m, 1H), 0.92 (d, J=6.7 Hz, 6H); HPLC ret.time 2.73 min, 10-99% CH₃CN, 5 min run; ESI-MS 403.3 m/z (MH⁺).

Another Example

148;4-Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide

4-Oxo-N-[5-(1-piperidylcarbonyl)-1H-indol-6-yl]-1H-quinoline-3-carboxamide(148) was synthesized following the general scheme above, coupling theacid (188-I) with piperidine. Overall yield (12%). HPLC ret. time 2.79min, 10-99% CH₃CN, 5 min run; ESI-MS 415.5 m/z (MH⁺).

Example 2 General Scheme

Specific Example

158; 4-Oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide

A mixture of N-(5-bromo-1H-indol-6-yl)-4-oxo-1H-quinoline-3-carboxamide(B-27-I) (38 mg, 0.1 mol), phenyl boronic acid (18 mg, 0.15 mmol),(dppf)PdCl₂ (cat.), and K₂CO₃ (100 μL, 2M solution) in DMF (1 mL) washeated in the microwave at 180° C. for 10 min. The reaction was filteredand purified by HPLC (10-99% CH₃CN/H₂O) to yield the product,4-oxo-N-(5-phenyl-1H-indol-6-yl)-1H-quinoline-3-carboxamide (158) (5 mg,13%). HPLC ret. time 3.05 min, 10-99% CH₃CN, 5 min run; ESI-MS 380.2 m/z(MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Compound of formula I Boronic acid 237 2-methoxyphenylboronic acid 3272-ethoxyphenylboronic acid 404 2,6-dimethoxyphenylboronic acid 15-chloro-2-methoxy-phenylboronic acid 342 4-isopropylphenylboronic acid347 4-(2-Dimethylaminoethylcarbamoyl)phenylboronic acid 653-pyridinylboronic acid

Example 3

27;N-[1-[2-[Methyl-(2-methylaminoacetyl)-amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide

To a solution ofmethyl-{[methyl-(2-oxo-2-{6-[(4-oxo-1,4-dihydro-quinoline-3-carbonyl)-amino]-indol-1-yl}-ethyl)-carbamoyl]-methyl}-carbamicacid tert-butyl ester (B-26-I) (2.0 g, 3.7 mmol) dissolved in a mixtureof CH₂Cl₂ (50 mL) and methanol (15 mL) was added HCl solution (60 mL,1.25 M in methanol). The reaction was stirred at room temperature for 64h. The precipitated product was collected via filtration, washed withdiethyl ether and dried under high vacuum to provide the HCl salt of theproduct,N-[1-[2-[methyl-(2-methylaminoacetyl)-amino]acetyl]-1H-indol-6-yl]-4-oxo-1H-quinoline-3-carboxamide(27) as a greyish white solid (1.25 g, 70%). ¹H-NMR (400 MHz, DMSO-d₆) δ13.20 (d, J=6.7 Hz, 1H), 12.68 (s, 1H), 8.96-8.85 (m, 1H), 8.35 (d,J=7.9 Hz, 1H), 7.91-7.77 (m, 3H), 7.64-7.54 (m, 3H), 6.82 (m, 1H), 5.05(s, 0.7H), 4.96 (s, 1.3H), 4.25 (t, J=5.6 Hz, 1.3H), 4.00 (t, J=5.7 Hz,0.7H), 3.14 (s, 2H), 3.02 (s, 1H), 2.62 (t, J=5.2 Hz, 2H), 2.54 (t,J=5.4 Hz, 1H); HPLC ret. time 2.36 min, 10-99% CH₃CN, 5 min run; ESI-MS446.5 m/z (MH⁺).

Phenols

Example 1 General Scheme

Specific Example

75;4-Benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide

To a mixture ofN-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428)(6.7 mg, 0.02 mmol) and Cs₂CO₃ (13 mg, 0.04 mmol) in DMF (0.2 mL) wasadded BnBr (10 uL, 0.08 mmol). The reaction mixture was stirred at roomtemperature for 3 h. The reaction mixture was filtered and purifiedusing HPLC to give4-benzyloxy-N-(3-hydroxy-4-tert-butyl-phenyl)-quinoline-3-carboxamide(275). ¹H NMR (400 MHz, DMSO-d₆) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s,1H), 8.43 (d, J=7.9 Hz, 1H), 7.79 (t, J=2.0 Hz, 2H), 7.56 (m, 1H),7.38-7.26 (m, 6H), 7.11 (d, J=8.4 Hz, 1H), 6.99 (dd, J=8.4, 2.1 Hz, 1H),5.85 (s, 2H), 1.35 (s, 9H). HPLC ret. time 3.93 min, 10-99% CH₃CN, 5 minrun; ESI-MS 427.1 m/z (MH⁺).

Another Example

15; N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide

N-(3-Hydroxy-4-tert-butyl-phenyl)-4-methoxy-quinoline-3-carboxamide(415) was synthesized following the general scheme above reactingN-(3-hydroxy-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (428)with methyl iodide. ¹H NMR (400 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.46 (s,1H), 8.99 (s, 1H), 8.42 (t, J=4.2 Hz, 1H), 7.95-7.88 (m, 2H), 7.61-7.69(m, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.10 (d, J=8.4 Hz, 1H), 6.96 (dd,J=8.4, 2.1 Hz, 1H), 4.08 (s, 3H), 1.35 (s, 9H); HPLC ret. time 3.46 min,10-99% CH₃CN, 5 min run; ESI-MS 351.5 m/z (MH⁺).

Example 2

476;N-(4-tert-Butyl-2-cyano-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide

To a suspension ofN-(4-tert-butyl-2-bromo-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide(C-27-I) (84 mg, 0.2 mmol), Zn(CN)₂ (14 mg, 0.12 mmol) in NMP (1 mL) wasadded Pd(PPh₃)₄ (16 mg, 0.014 mmol) under nitrogen. The mixture washeated in a microwave oven at 200° C. for 1 h, filtered and purifiedusing preparative HPLC to giveN-(4-tert-butyl-2-cyano-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide(476). ¹H NMR (400 MHz, DMSO-d₆) δ 13.00 (d, J=6.4 Hz, 1H), 12.91 (s,1H), 10.72 (s, 1H), 8.89 (d, J=6.8 Hz, 1H), 8.34 (d, J=8.2 Hz, 1H), 8.16(s, 1H), 7.85-7.75 (m, 2H), 7.56-7.54 (m, 1H), 7.44 (s, 1H), 1.35 (s,9H); HPLC ret. time 3.42 min, 10-100% CH₃CN, 5 min gradient; ESI-MS362.1 m/z (MH⁺).

Anilines

Example 1 General Scheme

Specific Example

60; N-(5-Amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

A mixture of[3-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-4-tert-butyl-phenyl]aminoformicacid tert-butyl ester (353) (33 mg, 0.08 mmol), TFA (1 mL) and CH₂Cl₂ (1mL) was stirred at room temperature overnight. The solution wasconcentrated and the residue was dissolved in DMSO (1 mL) and purifiedby HPLC (10-99% CH₃CN/H₂O) to yield the product,N-(5-amino-2-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (260)(15 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (d, J=6.6 Hz, 1H), 12.20(s, 1H), 10.22 (br s, 2H), 8.88 (d, J=6.8 Hz, 1H), 8.34 (d, J=7.8 Hz,1H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J=8.5, 2.4 Hz, 1H),1.46 (s, 9H); HPLC ret. time 2.33 min, 10-99% CH₃CN, 5 min run; ESI-MS336.3 m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Starting Intermediate Product  60 101 D-12-I 282 D-13-I  41 114 393D-16-I 157 D-15-I 356 D-17-I 399

Example 2 General Scheme

Specific Example

485;N-(3-Dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboximide

To a suspension ofN-(3-amino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (271)(600 mg, 1.8 mmol) in CH₂Cl₂ (15 mL) and methanol (5 mL) were addedacetic acid (250 μL) and formaldehyde (268 μL, 3.6 mmol, 37 wt % inwater). After 10 min, sodium cyanoborohydride (407 mg, 6.5 mmol) wasadded in one portion. Additional formaldehyde (135 μL, 1.8 mmol, 37 wt %in water) was added at 1.5 and 4.2 h. After 4.7 h, the mixture wasdiluted with ether (40 mL), washed with water (25 mL) and brine (25 mL),dried (Na₂SO₄), filtered, and concentrated. The resulting red-brown foamwas purified by preparative HPLC to affordN-(3-dimethylamino-4-tert-butyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide(485) (108 mg, 17%). ¹H NMR (300 MHz, CDCl₃) δ 13.13 (br s, 1H), 12.78(s, 1H), 8.91 (br s, 1H), 8.42 (br s, 1H), 8.37 (d, J=8.1 Hz, 1H),7.72-7.58 (m, 2H), 7.47-7.31 (m, 3H), 3.34 (s, 6H), 1.46 (s, 9H); HPLCret. time 2.15 min, 10-100% CH₃CN, 5 min run; ESI-MS 364.3 m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Starting Intermediate Product 69 117 160 462 282 409 41 98

Example 3 General Scheme

Specific Example

94; N-(5-Amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of 4-hydroxy-quinoline-3-carboxylic acid (A-1) (50 mg,0.26 mmol), HBTU (99 mg, 0.26 mmol) and DIEA (138 μL, 0.79 mmol) in THF(2.6 mL) was added 2-methyl-5-nitro-phenylamine (40 mg, 0.26 mmol). Themixture was heated at 150° C. in the microwave for 20 min and theresulting solution was concentrated. The residue was dissolved in EtOH(2 mL) and SnCl₂.2H₂O (293 mg, 1.3 mmol) was added. The reaction wasstirred at room temperature overnight. The reaction mixture was basifiedwith sat. NaHCO₃ solution to pH 7-8 and extracted with ethyl acetate.The combined organic layers were washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was dissolved in DMSO andpurified by HPLC (10-99% CH₃CN/H₂O) to yield the product,N-(5-amino-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (94) (6 mg,8%). HPLC ret. time 2.06 min, 10-99% CH₃CN, 5 min run; ESI-MS 294.2 m/z(MH⁺).

Another Example

17; N-(5-Amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide

N-(5-Amino-2-propoxy-phenyl)-4-oxo-1H-quinoline-3-carboxamide (17) wasmade following the general scheme above starting from4-hydroxy-quinoline-3-carboxylic acid (A-1) and5-nitro-2-propoxy-phenylamine. Yield (9%). HPLC ret. time 3.74 min,10-99% CH₃CN, 5 min run; ESI-MS 338.3 m/z (MH⁺).

Example 4 General Scheme

Specific Example

248; N-(3-Acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide

To a solution ofN-(3-amino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (167) (33mg, 0.11 mmol) and DIEA (49 μL, 0.28 mmol) in THF (1 mL) was addedacetyl chloride (16 μL, 0.22 mmol). The reaction was stirred at roomtemperature for 30 min. LCMS analysis indicated that diacylation hadoccurred. A solution of piperidine (81 μL, 0.82 mmol) in CH₂Cl₂ (2 mL)was added and the reaction stirred for a further 30 min at which timeonly the desired product was detected by LCMS. The reaction solution wasconcentrated and the residue was dissolved in DMSO and purified by HPLC(10-99% CH₃CN/H₂O) to yield the product,N-(3-acetylamino-4-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (248)(4 mg, 11%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.95 (d, J=6.6 Hz, 1H), 12.42(s, 1H), 9.30 (s, 1H), 8.86 (d, J=6.8 Hz, 1H), 8.33 (dd, J=8.1, 1.3 Hz,1H), 7.85-7.81 (m, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.55 (t, J=8.1 Hz, 1H),7.49 (dd, J=8.2, 2.2 Hz, 1H), 7.18 (d, J=8.3 Hz, 1H), 2.18 (s, 3H), 2.08(s, 3H); HPLC ret. time 2.46 min, 10-99% CH₃CN, 5 min run; ESI-MS 336.3m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Starting from X R² Product 260 CO Me 316 260 CO neopentyl 196 429 CO Me379 41 CO Me 232 101 CO Me 243 8 CO Me 149 271 CO₂ Et 127 271 CO₂ Me 14167 CO₂ Et 141 69 CO₂ Me 30 160 CO₂ Me 221 160 CO₂ Et 382 69 CO₂ Et 225282 CO₂ Me 249 282 CO₂ Et 472 41 CO₂ Me 471 101 CO₂ Me 239 101 CO₂ Et269 8 CO₂ Me 129 8 CO₂ Et 298 160 SO₂ Me 340

Example 5 General Scheme

Specific Example

4-Oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide

To a suspension ofN-[3-amino-5-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide(429) (500 mg 1.4 mmol) in 1,4-dioxane (4 mL) was added NMM (0.4 mL, 3.6mmol). P-Chloroethylsulfonyl chloride (0.16 mL, 1.51 mmol) was addedunder an argon atmosphere. The mixture was stirred at room temperaturefor 6½ h, after which TLC(CH₂Cl₂-EtOAc, 8:2) showed a new spot with avery similar R_(f) to the starting material. Another 0.5 eq. of NMM wasadded, and the mixture was stirred at room temperature overnight. LCMSanalysis of the crude mixture showed >85% conversion to the desiredproduct. The mixture was concentrated, treated with 1M HCl (5 mL), andextracted with EtOAc (3×10 mL) and CH₂Cl₂ (3×10 mL). The combinedorganic extracts were dried over Na₂SO₄, filtered, and concentrated toyield4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamideas an orange foam (0.495 g, 79%), which was used in the next stepwithout further purification. ¹H-NMR (d₆-Acetone, 300 MHz) δ 8.92 (s,1H), 8.41-8.38 (m, 1H), 7.94 (m, 2H), 7.78 (br s, 2H), 7.53-7.47 (m,1H), 7.30 (s, 1H), 6.87-6.79 (dd, J=9.9 Hz, 1H), 6.28 (d, J=16.5 Hz,1H), 6.09 (d, J=9.9 Hz, 1H); ESI-MS 436.4 m/z (MH⁻)

318;4-Oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide

A mixture of4-oxo-N-[3-(trifluoromethyl)-5-(vinylsulfonamido)phenyl]-1,4-dihydroquinoline-3-carboxamide(50 mg, 0.11 mmol), piperidine (18 μL, 1.6 eq) and LiClO₄ (20 mg, 1.7eq) was suspended in a 1:1 solution of CH₂Cl₂:isopropanol (1.5 mL). Themixture was refluxed at 75° C. for 18 h. After this time, LCMS analysisshowed >95% conversion to the desired product. The crude mixture waspurified by reverse-phase HPLC to provide4-oxo-N-[3-[2-(1-piperidyl)ethylsulfonylamino]-5-(trifluoromethyl)phenyl]-1H-quinoline-3-carboxamide(318) as a yellowish solid (15 mg, 25%). ¹H-NMR (d₆-Acetone, 300 MHz) δ8.92 (br s, 1H), 8.4 (d, J=8.1 Hz, 1H), 8.05 (br s, 1H), 7.94 (br s,1H), 7.78 (br s, 2H), 7.53-751 (m, 1H), 7.36 (br s, 1H), 3.97 (t, J=7.2Hz, 2H), 3.66 (t, J=8 Hz, 2H), 3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H);ESI-MS 489.1 m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Starting Intermediate Amine Product 429 morpholine 272 429 dimethylamine359 131 piperidine 133 131 morpholine 46

Example 6 General Scheme

Specific Example

258; N-Indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide

A mixture of N-(1-acetylindolin-6-yl)-4-oxo-1H-quinoline-3-carboxamide(233) (43 mg, 0.12 mmol), 1N NaOH solution (0.5 mL) and ethanol (0.5 mL)was heated to reflux for 48 h. The solution was concentrated and theresidue was dissolved in DMSO (1 mL) and purified by HPLC (10-99%CH₃CN—H₂O) to yield the product,N-indolin-6-yl-4-oxo-1H-quinoline-3-carboxamide (258) (10 mg, 20%). HPLCret. time 2.05 min, 10-99% CH₃CN, 5 min run; ESI-MS 306.3 m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Starting from Product Conditions Solvent DC-8-I 386 NaOH EtOH DC-9-I 10HCl EtOH 175 22 HCl EtOH 109 35 HCl EtOH 334 238 NaOH EtOH DC-10-I 105NaOH THF

Example 2 General Scheme

Specific Example

299;4-Oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide

A mixture of7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylicacid tert-butyl ester (183) (23 mg, 0.05 mmol), TFA (1 mL) and CH₂Cl₂ (1mL) was stirred at room temperature overnight. The solution wasconcentrated and the residue was dissolved in DMSO (1 mL) and purifiedby HPLC (10-99% CH₃CN—H₂O) to yield the product,4-oxo-N-(1,2,3,4-tetrahydroquinolin-7-yl)-1H-quinoline-3-carboxamide(299) (7 mg, 32%) HPLC ret. time 2.18 min, 10-99% CH₃CN, 5 min run;ESI-MS 320.3 m/z (MH⁺).

Another Example

300;N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide

N-(4,4-Dimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-4-oxo-1H-quinoline-3-carboxamide(300) was synthesized following the general scheme above starting from4,4-dimethyl-7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-1,2,3,4-tetrahydroquinoline-1-carboxylicacid tert-butyl ester (108). Yield (33%). ¹H NMR (400 MHz, DMSO-d₆) δ13.23 (d, J=6.6 Hz, 1H), 12.59 (s, 1H), 8.87 (d, J=6.8 Hz, 1H), 8.33 (d,J=7.7 Hz, 1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88(m, 2H), 1.30 (s, 6H); HPLC ret. time 2.40 min, 10-99% CH₃CN, 5 min run;ESI-MS 348.2 m/z (MH⁺).

Other

Example 1 General Scheme

Specific Example

163; 4-Oxo-1,4-dihydro-quinoline-3-carboxylic acid(4-aminomethyl-2′-ethoxy-biphenyl-2-yl)-amide

{2′-Ethoxy-2-[(4-oxo-1,4-dihydroquinoline-3-carbonyl)-amino]-biphenyl-4-ylmethyl}-carbamicacid tert-butyl ester (304) (40 mg, 0.078 mmol) was stirred in aCH₂Cl₂/TFA mixture (3:1, 20 mL) at room temperature for 1 h. Thevolatiles were removed on a rotary evaporator. The crude product waspurified by preparative HPLC to afford4-oxo-1,4-dihydroquinoline-3-carboxylix acid(4-aminomethyl-2′-ethoxybiphenyl-2-yl)amine (163) as a tan solid (14 mg.43%). ¹H NMR (300 MHz, DMSO-d₆) δ 12.87 (d, J=6.3 Hz, 1H), 11.83 (s,1H), 8.76 (d, J=6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.01 (dd,J=8.4 Hz, J=1.5 Hz, 1H), 7.75 (dt, J=8.1 Hz, J=1.2 Hz, 1H), 7.67 (d,J=7.8 Hz, 1H), 7.47-7.37 (m, 2H), 7.24 (s, 2H), 7.15 (dd, J=7.5 Hz,J=1.8 Hz, 1H), 7.10 (d, J=8.1 Hz, 1H), 7.02 (dt, J=7.5 Hz, J=0.9 Hz,1H), 4.09 (m, 2H), 4.04 (q, J=6.9 Hz, 2H), 1.09 (t, J=6.9 Hz, 3H); HPLCret. time 1.71 min, 10-100% CH₃CN, 5 min gradient; ESI-MS 414.1 m/z(MH⁺).

Another Example

390;N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide

N-[3-(Aminomethyl)-4-tert-butyl-phenyl]-4-oxo-1H-quinoline-3-carboxamide(390) was synthesized following the general scheme above starting from[5-[(4-oxo-1H-quinolin-3-yl)carbonylamino]-2-tert-butyl-phenyl]methylaminoformicacid tert-butyl ester (465). HPLC ret. time 2.44 min, 10-99% CH₃CN, 5min gradient; ESI-MS m/z 350.3 (M+H)⁺.

Example 2 General Scheme

Specific Example

3-(2-(4-(1-Amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one

(2-Methyl-2-{4-[2-oxo-2-(4-oxo-1,4-dihydro-quinolin-3-yl)-ethyl]-phenyl}-propyl)-carbamicacid tert-butyl ester (88) (0.50 g, 1.15 mmol), TFA (5 mL) and CH₂Cl₂ (5mL) were combined and stirred at room temerpature overnight. Thereaction mixture was then neutralized with 1N NaOH. The precipitate wascollected via filtration to yield the product3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one asa brown solid (651 mg, 91%). HPLC ret. time 2.26 min, 10-99% CH₃CN, 5min run; ESI-MS 336.5 m/z (MH⁺).

323;[2-Methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid methyl ester

Methyl chloroformate (0.012 g, 0.150 mmol) was added to a solution of3-(2-(4-(1-amino-2-methylpropan-2-yl)phenyl)acetyl)quinolin-4(1H)-one(0.025 g, 0.075 mmol), TEA (0.150 mmol, 0.021 mL) and DMF (1 mL) andstirred at room temperature for 1 h. Then piperidine (0.074 ml, 0.750mmol) was added and the reaction was stirred for another 30 min. Thereaction mixture was filtered and purified by preparative HPLC (10-99%CH₃CN—H₂O) to yield the product[2-methyl-2-[4-[(4-oxo-1H-quinolin-3-yl)carbonylamino]phenyl]-propyl]aminoformicacid methyl ester (323). ¹H NMR (400 MHz, DMSO-d₆) δ 12.94 (br s, 1H),12.44 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J=8.2, 1.1 Hz, 1H), 7.82 (t,J=8.3 Hz, 1H), 7.76 (d, J=7.7 Hz, 1H), 7.67 (d, J=8.8 Hz, 2H), 7.54 (t,J=8.1 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.02 (t, J=6.3 Hz, 1H), 3.50 (s,3H), 3.17 (d, J=6.2 Hz, 2H), 1.23 (s, 6H); HPLC ret. time 2.93 min,10-99% CH₃CN, 5 min run; ESI-MS 394.0 m/z (MH⁺).

The table below lists other examples synthesized following the generalscheme above.

Product Chloroformate 119 Ethyl chloroformate 416 Propyl chloroformate460 Butyl chloroformate 251 Isobutyl chloroformate 341 Neopentylchloroformate 28 2-methoxyethyl chloroformate 396(tetrahydrofuran-3-yl)methyl chloroformate

Example 3 General Scheme

Specific Example

73-I; N-(1-Aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide

To a solution of[7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidtert-butyl ester (273) (250 mg, 0.6 mmol) in dichloromethane (2 mL) wasadded TFA (2 mL). The reaction was stirred at room temperature for 30min. More dichloromethane (10 mL) was added to the reaction mixture andthe solution was washed with sat. NaHCO₃ solution (5 mL). A precipitatebegan to form in the organic layer so the combined organic layers wereconcentrated to yieldN-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (185mg, 93%). HPLC ret. time 1.94 min, 10-99% CH₃CN, 5 min run; ESI-MS 334.5m/z (MH⁺).

159; [7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformicacid methyl ester

To a solution ofN-(1-aminotetralin-7-yl)-4-oxo-1H-quinoline-3-carboxamide (273-I) (65mg, 0.20 mmol) and DIEA (52 μL, 0.29 mmol) in methanol (1 mL) was addedmethyl chloroformate (22 μL, 0.29 mmol). The reaction was stirred atroom temperature for 1 h. LCMS analysis of the reaction mixture showedpeaks corresponding to both the single and bis addition products.Piperidine (2 mL) was added and the reaction was stirred overnight afterwhich only the single addition product was observed. The resultingsolution was filtered and purified by HPLC (10-99% CH₃CN—H₂O) to yieldthe product,[7-[(4-oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidmethyl ester (159) (27 mg, 35%). HPLC ret. time 2.68 min, 10-99% CH₃CN,5 min run; ESI-MS 392.3 m/z (MH⁺).

Another Example

482; [7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformicacid ethyl ester

[7-[(4-Oxo-1H-quinolin-3-yl)carbonylamino]tetralin-1-yl]aminoformic acidethyl ester (482) was synthesized following the general scheme above,from amine (273-I) and ethyl chloroformate. Overall yield (18%). HPLCret. time 2.84 min, 10-99% CH₃CN, 5 min run; ESI-MS 406.5 m/z (MH⁺).

Set forth below is the characterizing data for compounds of the presentinvention prepared according to the above Examples.

TABLE 2 Cmd LC-MS LC-RT No. M + 1 min 1 444.3 3.19 2 350.1 3.8 3 455.33.75 4 350.3 2.81 5 337.3 2.76 6 351.4 3 7 472.3 3.6 8 307.1 1.21 9344.1 2.43 10 334.2 2.2 11 408.1 2.91 12 383.1 2.63 13 346.3 3.48 14394.3 3.07 15 296.3 2.68 16 307.3 3.38 17 338.3 3.74 18 352.9 3.62 19316.3 2.71 20 371.3 3.53 21 421.1 2.66 22 332.2 2.21 23 457.5 3.56 24398.3 3.13 25 397.1 2.38 26 348.1 2.51 27 446.2 2.33 28 438.4 2.9 29307.1 3.32 30 379.1 2.62 31 278.9 3.03 32 338.2 3 33 303.9 2.83 34 397.14.19 35 362.2 2.53 36 307.3 3.25 37 303.9 2.98 38 380.3 3.33 39 480.53.82 40 309.1 2.46 41 321.1 1.88 42 460.0 3.71 43 457.5 3.6 44 336.12.95 45 308.1 3.18 46 490.1 1.89 47 375.3 3.33 48 317.1 3.06 49 400.12.88 50 307.3 3.08 51 521.5 3.79 52 354.1 3.02 53 266.1 1.99 54 323.32.97 55 366.3 2.6 56 335.4 3.18 57 403.1 2.86 58 364.3 3.02 59 412.13.31 60 422.2 3.53 61 293.1 3.05 62 349.1 3.4 63 376.1 2.89 64 321.12.31 65 381.5 1.85 66 345.1 3.32 67 332.3 3.17 68 398.1 2.85 69 322.52.37 70 341.1 2.15 71 426.1 2.6 72 293.1 3.27 73 380.9 2.4 74 334.1 3.3275 316.3 2.43 76 376.1 2.97 77 322.5 2.93 78 344.1 2.38 79 372.1 3.07 80295.3 2.78 81 336.3 2.73 82 350.3 2.11 83 365.1 2.76 84 280.3 2.11 85408.0 3.25 86 370.3 2.08 87 357.1 3.5 88 436.3 3.37 89 303.9 3.1 90321.1 3.43 91 355.2 3.47 92 295.2 3.84 93 371.0 2.75 94 294.2 2.06 95290.1 2.78 96 343.0 2.75 97 402.1 2.59 98 349.1 1.96 99 334.1 3.13 100303.9 2.63 101 322.5 2.35 102 443.1 3.97 103 411.2 3.85 104 318.0 2.94105 322.2 2.4 106 350.3 2.86 107 420.2 3.37 108 448.2 3.77 109 404.53.17 110 303.9 2.75 111 333.1 3 112 348.5 3.07 113 318.3 3.02 114 499.23.74 115 330.1 2.67 116 320.2 3.18 117 349.1 1.32 118 379.1 2.61 119408.4 3.07 120 309.1 2.93 121 333.1 3.69 122 325.1 2.66 123 330.1 2.64124 378.3 3.4 125 294.3 2.21 126 411.1 3.06 127 408.5 3.22 128 369.13.53 129 365.1 1.74 130 440.2 3.57 131 313.0 2.4 132 365.9 2.73 133488.1 1.97 134 402.1 2.25 135 384.1 2.94 136 393.1 4.33 137 580.5 4.1138 376.1 2.98 139 408.0 3.17 140 346.1 4 141 366.3 2.89 142 321.3 3.58143 355.2 3.45 144 281.3 2.49 145 376.2 2.98 146 306.3 2.51 147 376.33.27 148 415.5 2.79 149 349.1 1.45 150 430.0 3.29 151 360.0 3 152 322.32.31 153 425.1 4.52 154 401.3 3.77 155 266.1 2.11 156 424.1 3.12 157321.0 2.13 158 380.2 3.05 159 392.3 2.68 160 321.1 1.34 161 409.2 3.82162 296.3 2.61 163 413.1 1.71 164 333.1 3.33 165 344.1 2.41 166 398.12.83 167 294.3 2.12 168 265.9 1.96 169 318 2.98 170 300.3 3.08 171 408.03.08 172 396.0 3.14 173 280.3 2.14 174 388.0 2.58 175 374.2 2.85 176349.1 3.38 177 337.1 3.5 178 413.3 4 179 308.5 2.33 180 307.3 3.08 181354.1 2.97 182 358.1 2.89 183 420.3 3.47 184 372.3 2.66 185 414.1 2.96186 372.3 3.59 187 346.3 2.9 188 376.2 2.95 189 370.9 3.38 190 392.03.09 191 316.3 2.1 192 280.3 2.13 193 326.3 3.02 194 290.1 2.98 195280.3 2.14 196 434.5 3.38 197 334.1 3.15 198 283.1 3 199 354.1 2.96 200335.5 2.49 201 303.9 3.08 202 404.0 3.19 203 394.3 3.42 204 349.3 3.32205 455.5 3.74 206 386.1 3.5 207 390.3 2.71 208 429.7 3.89 209 294.12.39 210 385.2 3.72 211 351.3 3.53 212 360.9 2.45 213 408.0 3.3 214358.1 2.7 215 265.3 3.07 216 305.3 2.27 217 305.3 2.41 218 413.2 3.98219 266.9 2.48 220 409.0 3.35 221 379.1 2.68 222 324.3 3.27 223 386.13.14 224 466.3 3.08 225 393.1 2.75 226 306.1 3.6 227 381.1 2.24 228371.1 2.84 229 311.1 2.93 230 318.1 2.81 231 471.3 3.41 232 363.1 2.57233 348.5 2.75 234 372.3 3.2 235 308.4 2.12 236 333.1 3.35 237 410.32.96 238 489.4 2.78 239 379.0 2.62 240 370.9 3.65 241 316.3 2.61 242348.3 3.08 243 363.0 2.44 244 358.1 3.48 245 425.1 3.69 246 292.9 3.2247 432.1 3.23 248 336.3 2.46 249 365.0 2.54 250 352.3 2.53 251 436.23.38 252 368.9 3.17 253 424.1 3.25 254 340.1 3.08 255 526.5 3.89 256306.1 2.4 257 297.3 3.28 258 306.3 2.05 259 360.3 3.46 260 336.3 2.33261 368.1 3.08 262 352.3 2.7 263 372.9 3.69 264 353.1 3.42 265 354.9 3.4266 405.3 4.05 267 357.1 3.43 268 400.3 6.01 269 393.0 2.75 270 329.33.02 271 336.5 2.75 272 524.1 1.87 273 434.5 3.17 274 493.5 3.46 275427.1 3.93 276 414.3 2.81 277 358.1 2.89 278 408.1 3.09 279 386.1 2.88280 316.3 2.06 281 293.1 3.22 282 307.1 1.22 283 370.1 3 284 305.3 2.57285 376.1 2.88 286 319.1 3.35 287 411.2 4.15 288 413.3 3.8 289 297.33.25 290 382.1 3.19 291 371.0 3.57 292 391.1 3.69 293 330.3 3.05 294303.9 2.67 295 334.3 2.26 296 365.3 3.6 297 358.3 3.26 298 379.1 1.91299 320.3 2.18 300 348.2 2.4 301 346.3 2.26 302 370.1 2.28 303 362.22.51 304 513.2 3.66 305 370.1 2.98 306 384.1 3.11 307 374.0 3.05 308304.1 2.71 309 316.3 2.83 310 320.1 3.73 311 344.9 3.43 312 400.1 2.86313 358.1 2.8 314 335.1 3.52 315 293.1 2.9 316 378.5 2.84 317 333.2 2.91318 522.1 1.8 319 373.3 3.59 320 360.1 3.5 321 453.5 3.12 322 349.3 3.7323 394.0 2.93 324 320.1 3.81 325 321.3 3.22 326 418.0 2.5 327 424.2 3.2328 307.1 2.76 329 396.3 3.72 330 299.3 3.02 331 308.3 2.25 332 288.02.5 333 379.1 2.61 334 531.3 3.26 335 322.3 2.41 336 321.5 3.52 337407.5 3.37 338 318.3 2.73 339 329.0 2.75 340 399.1 2.6 341 450.4 3.56342 422.3 3.41 343 403.3 2.73 344 384.1 3.07 345 322.2 2.96 346 333.13.38 347 494.5 1.97 348 384.1 3.12 349 405.3 2.85 350 315.1 3.23 351332.3 3.18 352 447.5 3.17 353 436.3 3.53 354 390.3 2.36 355 370.9 3.37356 335.0 1.81 357 346.3 3.08 358 338.2 3.15 359 482.1 1.74 360 331.33.07 361 400.1 2.91 362 355.5 3.46 363 388.1 2.92 364 330.3 2.68 365307.1 2.6 366 408.1 3.09 367 408.0 3.14 368 338.2 2.33 369 358.1 3.29370 299.1 3.03 371 365.0 3.27 372 362.1 2.66 373 305.3 3.38 374 350.33.01 375 319.3 3.4 376 382.3 3.48 377 340.2 3.08 378 310.3 2.07 379389.0 2.53 380 309.3 3.02 381 360.2 3.18 382 393.1 2.84 383 332.3 3.2384 376.1 2.87 385 393.9 3.32 386 334.3 2.3 387 347.1 3.22 388 424.1 3.3389 355.3 3.65 390 350.3 2.44 391 396.1 3.43 392 300.3 2.86 393 399.42.12 394 293.1 3.17 395 433.5 4.21 396 464.4 2.97 397 341.3 3.45 398434.3 3.1 399 335.0 1.75 400 351.3 2.11 401 368.1 3.09 402 342.1 2.96403 423.1 4.45 404 440.3 2.87 405 299.3 3.16 406 547.3 3.74 407 371.33.8 408 295.3 2.9 409 335.1 1.82 410 432.1 3.41 411 299.1 3.17 412 376.22.93 413 357.1 3.37 414 305.3 2.11 415 351.5 3.44 416 422.4 3.23 417396.0 2.67 418 308.3 2.23 419 322.3 2.48 420 379.1 3.2 421 419.2 3.82422 333.1 2.48 423 376.3 3.02 424 374.0 3.06 425 306.1 3.53 426 371.32.95 427 420.3 3.3 428 337.2 3.32 429 348.3 2.98 430 321.3 3.22 431280.3 2.09 432 382.1 3.22 433 393.2 3.71 434 293.1 3.12 435 376.3 3.22436 400.1 2.88 437 309.3 2.82 438 427.5 3.87 439 295.3 2.8 440 395.33.61 441 425.0 2.67 442 412.3 3.35 443 317.3 2.45 444 379.2 3.42 445305.5 3.08 446 353.1 2.85 447 290.1 2.88 448 321.3 3.5 449 279.1 3.22450 308.1 1.97 451 318.1 3.28 452 290.1 3.32 453 314.1 2.75 454 355.13.58 455 398.1 3.6 456 365.1 3.65 457 350.3 2.26 458 381.2 3.19 459279.3 2.9 460 436.2 3.38 461 341.3 3.23 462 349.1 1.9 463 292.1 3.35 464409.4 4.03 465 450.5 3.65 466 349.3 3.5 467 307.3 2.98 468 279.1 2.98469 409.1 3.69 470 373.3 3.64 471 379.0 2.73 472 379.0 2.67 473 363.33.64 474 336.3 2.8 475 334.3 3.23 476 362.1 3.42 477 283.9 2.8 478 360.33.44 479 334.3 2.59 480 323.5 3.22 481 315.3 3.25 482 406.5 2.84 483409.5 4.35 484 349.1 2.16 485 363.1 2.15NMR data for selected compounds is shown below in Table 2-A:

Cmpd No. NMR Data 2 1H NMR (300 MHz, CDCl₃) δ 12.53 (s, 1H), 11.44 (brd, J = 6.0 Hz, 1H), 9.04 (d, J = 6.7 Hz, 1H), 8.43 (d, J = 7.8 Hz, 1H),7.51 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 7.33-7.21 (m, 3H),7.10 (d, J = 8.2 Hz, 1H), 3.79 (s, 3H), 1.36 (s, 9H) 5 H NMR (400 MHz,DMSO-d6) δ 12.94 (bs, 1H), 12.41 (s, 1H), 8.88 (s, 1H), 8.34 (dd, J = 8,1 Hz, 1H), 7.82 (ddd, J = 8, 8.1 Hz, 1H), 7.75 (d, J = 8 Hz, 1H), 7.64(dd, J = 7.2 Hz, 2H), 7.54 (ddd, J = 8, 8.1 Hz, 1H), 7.35 (dd, J = 7.2Hz, 2H), 4.66 (t, J = 5 Hz, 1H), 3.41 (d, J = 5 Hz, 2H), 1.23 (s, 6H). 81H NMR (CD3OD, 300 MHz) δ 8.86 (s, 1H), 8.42 (d, J = 8.5 Hz, 1H), 7.94(s, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.67 (d, J = 8.3 Hz, 1H), 7.54-7.47(m, 2H), 7.38 (d, J = 8.5 Hz, 1H), 2.71 (q, J = 7.7 Hz, 2H), 1.30 (t, J= 7.4 Hz, 3H). 10 H NMR (400 MHz, DMSO-d6) δ 13.02 (d, J = 6.4 Hz, 1H),12.58 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H),7.89-7.77 (m, 3H), 7.56 (t, J = 8.1 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H),7.26 (d, J = 8.4 Hz, 1H), 3.23 (m, 2H), 2.81 (m, 2H), 1.94 (m, 2H), 1.65(m, 2H) 13 H NMR (400 MHz, DMSO-d6) δ 13.05 (bs, 1H), 12.68 (s, 1H),8.89 (s, 1H), 8.35 (t, J = 2.5 Hz, 1H), 8.32 (d, J = 1.1 Hz, 1H),7.85-7.76 (m, 3H), 7.58-7.54 (m, 2H), 1.47 (s, 9H) 14 H NMR (400 MHz,DMSO-d6) δ 1.32 (s, 9H), 3.64 (s, 3H), 7.36 (d, J = 8.4 Hz, 1H), 7.55(m, 3H), 7.76 (d, J = 8.0 Hz, 1H), 7.83 (m, 1H), 8.33 (d, J = 7.0 Hz,1H), 8.69 (s, 1H), 8.87 (d, J = 6.7 Hz, 1H), 12.45 (s, 1H), 12.97 (s,1H) 27 H NMR (400 MHz, DMSO-d6) δ 13.20 (d, J = 6.7 Hz, 1H), 12.68 (s,1H), 8.96-8.85 (m, 4H), 8.35 (d, J = 7.9 Hz, 1H), 7.91-7.77 (m, 3H),7.64-7.54 (m, 3H), 6.82 (m, 1H), 5.05 (s, 0.7H), 4.96 (s, 1.3H), 4.25(t, J = 5.6 Hz, 1.3H), 4.00 (t, J = 5.7 Hz, 0.7H), 3.14 (s, 2H), 3.02(s, 1H), 2.62 (t, J = 5.2 Hz, 2H), 2.54 (t, J = 5.4 Hz, 1H) 29 H NMR(400 MHz, CDCl₃) δ 9.09 (s, 1H), 8.62 (dd, J = 8.1 and 1.5 Hz, 1H),7.83-7.79 (m, 3H), 7.57 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H),7.14 (t, J = 7.4 Hz, 2H), 5.05 (m, 1H), 1.69 (d, J = 6.6 Hz, 6H) 32 HNMR (400 MHz, DMSO-d6) δ 12.93 (d, J = 6.6 Hz, 1H), 12.74 (s, 1H), 11.27(s, 1H), 8.91 (d, J = 6.7 Hz, 1H), 8.76 (s, 1H), 8.37 (d, J = 8.1 Hz,1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.70 (s, 1H),7.54 (t, J = 8.1 Hz, 1H), 7.38 (m, 1H), 6.40 (m, 1H) 33 H NMR (400 MHz,DMSO-d6) δ 12.92 (s, 1H), 12.47 (s, 1H), 11.08 (s, 1H), 8.90 (s, 1H),8.35 (dd, J = 8.1, 1.1 Hz, 1H), 8.20 (t, J = 0.8 Hz, 1H), 7.83 (t, J =8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.50(d, J = 8.4 Hz, 1H), 7.30 (t, J = 2.7 Hz, 1H), 7.06 (dd, J = 8.4, 1.8Hz, 1H), 6.39 (m, 1H) 35 H NMR (400 MHz, DMSO-d6) δ 13.01 (d, J = 6.7Hz, 1H), 12.37 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1, 1.3Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 8.2 Hz, 1H), 7.54 (t, J= 8.1 Hz, 1H), 7.36 (s, 1H),, 7.19 (d, J = 8.4 Hz, 1H), 7.08 (d, J = 8.2Hz, 1H), 3.29 (m, 2H), 1.85 (m, 1H), 1.73-1.53 (m, 3H), 1.21 (s, 3H),0.76 (t, J = 7.4 Hz, 3H) 43 H NMR (400 MHz, DMSO-d6) δ 12.77 (s, 1H),11.94 (s, 1H), 9.56 (s, 1H), 8.81 (s, 1H), 8.11 (dd, J = 8.2, 1.1 Hz,1H), 7.89 (s, 1H), 7.79-7.75 (m, 1H), 7.70 (d, J = 7.7 Hz, 1H),7.49-7.45 (m, 1H), 7.31 (t, J = 8.1 Hz, 1H), 7.00 (s, 1H), 6.93-6.87 (m,3H), 4.07 (q, J = 7.0 Hz, 2H), 1.38 (s, 9H), 1.28 (t, J = 7.0 Hz, 3H) 47H NMR (400 MHz, DMSO-d6) δ 1.24 (d, J = 6.9 Hz, 6H), 3.00 (m, 1H), 7.55(m, 3H), 7.76 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.26 (d, J = 8.2 Hz,1H), 8.33 (d, J = 9.2 Hz, 1H), 8.89 (s, 1H), 12.65 (s, 1H), 12.95 (s,1H) 56 H NMR (400 MHz, DMSO-d6) δ 12.81 (d, J = 6.7 Hz, 1H), 12.27 (s,1H), 9.62 (s, 1H), 8.82 (d, J = 6.7 Hz, 1H), 8.32 (dd, J = 8.2, 1.3 Hz,1H), 8.07 (s, 1H), 7.80 (t, J = 8.4 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H),7.52 (t, J = 8.1 Hz, 1H), 6.58 (s, 1H), 2.62 (m, 4H), 1.71 (m, 4H) 58 HNMR (400 MHz, DMSO-d6) δ 12.95 (d, J = 6.6 Hz, 1H), 12.39 (s, 1H), 8.86(d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.3 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H),7.75 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.29 (d, J = 2.5 Hz,1H), 7.07 (dd, J = 8.7, 1.3 Hz, 1H), 6.91 (dd, J = 8.8, 2.5 Hz, 1H),5.44 (br s, 2H) 64 H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 12.41 (s,1H), 10.63 (s, 1H), 10.54 (s, 1H), 8.86 (s, 1H), 8.33 (d, J = 8.1 Hz,1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.69 (s, 1H),7.54 (t, J = 8.1 Hz, 1H), 7.04 (d, J = 8.3 Hz, 1H), 6.90 (d, J = 8.3 Hz,1H) 69 H NMR (400 MHz, DMSO-d6) δ 13.06 (d, J = 6.5 Hz, 1H), 12.51 (s,1H), 8.88 (d, J = 6.6 Hz, 1H), 8.33 (dd, J = 8.1, 1.0 Hz, 1H), 7.85-7.74(m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.38 (dd, J = 8.4, 1.9 Hz, 1H), 7.32(d, J = 8.5 Hz, 1H), 3.03 (septet, J = 6.8 Hz, 1H), 1.20 (d, J = 6.7 Hz,6H) 76 1H-NMR (CDCl3, 300 MHz) δ 8.84 (d, J = 6.6 Hz, 1H), 8.31 (d, J =6.2 Hz, 1H), 8.01 (d, J = 7.9 Hz, 1H), 7.44-7.13 (m, 8H), 6.78 (d, J =7.5 Hz, 1H). 77 H NMR (400 MHz, DMSO-d6) δ 6.40 (m, 1H), 7.36 (t, J =2.7 Hz, 1H), 7.43 (d, J = 11.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.80(m, 2H), 8.36 (d, J = 9.2 Hz, 1H), 8.65 (d, J = 6.8 Hz, 1H), 8.91 (s,1H), 11.19 (s, 1H), 12.72 (s, 1H), 12.95 (s, 1H) 88 H NMR (400 MHz,DMSO-d6) δ 12.96 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 8.89 (d, J = 6.7Hz, 1H), 8.33 (dd, J = 8.1, 1.2 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76(d, J = 7.8 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H),7.34 (d, J = 8.7 Hz, 2H), 6.67 (t, J = 6.3 Hz, 1H), 3.12 (d, J = 6.3 Hz,2H), 1.35 (s, 9H), 1.22 (s, 6H) 90 1H NMR (400 MHz, DMSO-d6) δ 11.98 (s,1H), 8.89 (s, 1H), 8.34 (dd, J = 8.2, 1.1 Hz, 1H), 7.84-7.75 (m, 2H),7.59 (dd, J = 7.8, 1.5 Hz, 1H), 7.55-7.51 (m, 1H), 7.42 (dd, J = 7.9,1.5 Hz, 1H), 7.26-7.21 (m, 1H), 7.19-7.14 (m, 1H), 1.43 (s, 9H) 96 1HNMR (400 MHz, DMSO-d6) δ 12.58 (s, 1H), 11.11 (s, 1H), 8.89 (s, 1H),8.35 (dd, J = 8.1, 1.1 Hz, 1H), 8.22 (d, J = 1.5 Hz, 1H), 7.83-7.74 (m,2H), 7.56-7.51 (m, 2H), 7.30 (d, J = 2.3 Hz, 1H), 7.13 (dd, J = 8.5, 1.8Hz, 1H), 4.03 (d, J = 0.5 Hz, 2H) 103 H NMR (400 MHz, DMSO-d6) δ 1.37(s, 9H), 1.38 (s, 9H), 7.08 (s, 1H), 7.17 (s, 1H), 7.74 (m, 1H), 7.86(m, 1H), 7.98 (dd, J = 9.2, 2.9 Hz, 1H), 8.90 (d, J = 6.7 Hz, 1H), 9.21(s, 1H), 11.71 (s, 1H), 13.02 (d, J = 6.7 Hz, 1H) 104 1H NMR (400 MHz,DMSO-d6) δ 12.93 (d, J = 6.6 Hz, 1H), 12.41 (s, 1H), 10.88 (s, 1H), 8.88(d, J = 6.7 Hz, 1H), 8.36-8.34 (m, 1H), 8.05 (d, J = 0.8 Hz, 1H),7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.35 (d, J = 8.3 Hz, 1H), 7.01(dd, J = 8.4, 1.9 Hz, 1H), 6.07-6.07 (m, 1H), 2.37 (s, 3H) 107 H NMR(400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.1Hz, 1H), 7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.57-7.51(m, 3H), 7.15 (d, J = 8.3 Hz, 1H), 4.51 (s, 2H), 3.56 (t, J = 5.7 Hz,2H), 2.75 (t, J = 5.5 Hz, 2H), 1.44 (s, 9H) 109 H NMR (400 MHz, DMSO-d6)δ 12.97 (br s, 1H), 12.45 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1Hz, 1H), 7.88 (s, 1H), 7.82 (t, J = 8.4 Hz, 1H), 7.75 (d, J = 7.7 Hz,1H), 7.54 (t, J = 8.1 Hz, 1H), 7.43 (m, 1H), 7.31 (d, J = 8.5 Hz, 1H),4.01 (m, 1H), 3.41 (m, 1H), 2.21 (s, 3H), 1.85 (m, 1H), 1.68-1.51 (m,3H), 1.23 (s, 3H), 0.71 (t, J = 7.4 Hz, 3H) 113 1H NMR (400 MHz,DMSO-d6) δ 12.92 (d, J = 6.6 Hz, 1H), 12.46 (s, 1H), 10.72 (d, J = 1.5Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 8.35 (dd, J = 8.1, 1.2 Hz, 1H), 8.13(d, J = 1.5 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.44 (d, J =8.4 Hz, 1H), 7.07-7.04 (m, 2H), 2.25 (d, J = 0.9 Hz, 3H) 114 1H NMR (300MHz, DMSO-d6): δ 12.65 (d, J = 6.9 Hz, 1H), 11.60 (s, 1H), 9.33 (s, 1H),8.71 (d, J = 6.6 Hz, 1H), 8.36 (d, J = 1.8 Hz, 1H), 8.03 (d, J = 7.8 Hz,1H), 7.66 (t, J = 7.2 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.38 (t, J =7.8 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.12 (m, 2H), 6.97 (m, 3H), 3.97(m, 2H), 1.45 (s, 9H), 1.06 (t, J = 6.6 Hz, 3H). 126 H NMR (400 MHz,DMSO-d6) δ 12.94 (s, 1H), 12.33 (s, 1H), 9.49 (s, 1H), 8.88 (s, 1H),8.35 (dd, J = 8.7, 0.5 Hz, 1H), 7.86-7.82 (m, 1H), 7.77 (d, J = 7.8 Hz,,7.58-7.54 (m, 1H), 7.40 (d, J = 2.2 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H),6.98 (dd, J = 8.4, 2.2 Hz, 1H), 3.67 (s, 2H), 3.51-3.47 (m, 2H),3.44-3.41 (m, 2H), 3.36 (s, 3H), 1.33 (s, 6H) 127 H NMR (400 MHz,DMSO-d6) δ 1.23 (t, J = 7.0 Hz, 3H), 1.32 (s, 9H), 4.10 (q, J = 7.0 Hz,2H), 7.36 (d, J = 8.5 Hz, 1H), 7.54 (m, 3H), 7.76 (d, J = 7.9 Hz, 1H),7.82 (m, 1H) 8.33 (d, J = 9.2 Hz, 1H), 8.64 (s, 1H), 8.87 (s, 1H), 12.45(s, 1H), 12.99 (s, 1H) 129 1H-NMR (CD3OD, 300 MHz) δ 8.83 (s, 1H), 8.41(d, J = 8.1 Hz, 1H), 7.80 (m, 2H), 7.65 (d, J = 8.1 Hz, 1H), 7.55 (m,2H), 7.22 (d, J = 8.1 Hz, 1H), 3.76 (s, 3H, OMe), 2.62 (q, J = 7.5 Hz,2H), 1.21 (t, J = 7.5 Hz, 3H). 131 1H NMR (300 MHz, DMSO-d6) δ 12.37 (s,1H), 8.81 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.77 (m, 2H), 7.52 (t, J =7.2 Hz, 1H), 7.09 (s, 1H), 6.74 (s, 1H), 6.32 (s, 1H), 5.47 (s, 2H). 1351H-NMR (CDCl3, 300 MHz) δ 8.86 (d, J = 6.6 Hz, 1H), 8.32 (d, J = 6.2 Hz,1H), 8.07 (d, J = 7.9 Hz, 1H), 7.47-7.24 (m, 6H), 6.95-6.83 (m, 3H),5.95 (s, 2H). 136 H NMR (400 MHz, DMSO-d6) δ 1.29 (s, 9H), 1.41 (s, 9H),7.09 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.57 (t, J = 8.1 Hz,1H), 7.77 (d, J = 7.8 Hz, 1H), 7.85 (t, J = 8.4 Hz, 1H), 8.36 (d, J =9.5 Hz, 1H), 8.93 (d, J = 6.8 Hz, 1H), 9.26 (s, 1H), 12.66 (s, 1H),13.04 (d, J = 6.6 Hz, 1H) 141 H NMR (400 MHz, DMSO-d6) δ 12.96 (d, J =6.6 Hz, 1H), 12.42 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (dd, J = 8.1,1.2 Hz, 1H), 7.85-7.75 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.46 (dd, J =8.2, 2.2 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H),2.18 (s, 3H), 1.27 (t, J = 7.1 Hz, 3H) 143 H NMR (400 MHz, DMSO-d6) δ12.96 (d, J = 6.8 Hz, 1H), 12.56 (s, 1H), 9.44 (s, 1H), 8.87 (d, J = 6.8Hz, 1H), 8.34 (dd, J = 8.2, 1.3 Hz, 1H), 8.08 (d, J = 7.4 Hz, 1H), 7.83(t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H),7.00 (d, J = 13.3 Hz, 1H), 1.34 (s, 9H) 150 1H-NMR (DMSO d6, 300 MHz) δ8.86 (d, J = 6.9 Hz, 1H), 8.63 (s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.86(d, J = 8.7 Hz, 2H), 7.82-7.71 (m, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.52(td, J = 1.2 Hz, 1H). 157 1H-NMR (CD3OD, 300 MHz) δ 8.91 (s, 1H), 8.57(s, 1H), 8.45 (d, J = 8.3 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J= 9.0 Hz, 1H), 7.57 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.16(d, J = 6.0 Hz, 1H), 3.08 (s, 3H, NMe), 2.94 (q, J = 7.4 Hz, 2H), 1.36(t, J = 7.4 Hz, 3H). 161 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 12.41(s, 1H), 8.88 (s, 1H),, 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.84-7.80 (m,1H), 7.75 (d, J = 7.9 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H),, 7.44 (s, 1H),7.19 (s, 2H), 4.13 (t, J = 4.6 Hz, 2H), 3.79 (t, J = 4.6 Hz, 2H), 3.54(q, J = 7.0 Hz, 2H), 1.36 (s, 9H), 1.15 (t, J = 7.0 Hz, 3H) 163 1H-NMR(300 MHz, DMSO-d6) δ 12.87 (d, J = 6.3 Hz, 1H), 11.83 (s, 1H), 8.76 (d,J = 6.3 Hz, 1H), 8.40 (s, 1H), 8.26 (br s, 2H), 8.08 (dd, J = 8.4 Hz, J= 1.5 Hz, 1H), 7.75(m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.47-7.37 (m, 2H),7.24 (d, J = 0.9 Hz, 1H), 7.15 (dd, J = 7.5 Hz, J = 1.8 Hz, 1H), 7.10(d, J = 8.1 Hz, 1H), 7.02 (dt, J = 7.5 Hz, J = 0.9 Hz, 1H), 4.07 (m,4H), 1.094 (t, J = 6.9 Hz, 3H). 167 H NMR (400 MHz, DMSO-d6) δ 2.03 (s,3H), 4.91 (s, 2H), 6.95 (m, 3H), 7.53 (m, 1H), 7.75 (d, J = 8.2 Hz, 1H),7.81 (m, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.84 (s, 1H), 12.20 (s, 1H),12.90 (s, 1H) 169 1H NMR (400 MHz, DMSO-d6) δ 12.94 (d, J = 5.3 Hz, 1H),12.51 (s, 1H), 8.89 (d, J = 6.3 Hz, 1H), 8.36 (dd, J = 8.1, 1.1 Hz, 1H),8.06 (t, J = 0.7 Hz, 1H), 7.85-7.75 (m, 2H), 7.57-7.51 (m, 2H), 7.28 (d,J = 3.1 Hz, 1H), 7.24 (dd, J = 8.4, 1.8 Hz, 1H), 6.39 (dd, J = 3.1, 0.8Hz, 1H), 3.78 (s, 3H) 178 1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H),8.89 (d, J = 6.8 Hz, 1H), 8.65 (dd, J = 8.1, 1.6 Hz, 1H), 8.19 (dd, J =8.2, 1.3 Hz, 1H), 7.80-7.71 (m, 2H), 7.48-7.44 (m, 2H), 7.24-7.20 (m,1H), 7.16-7.09 (m, 2H), 7.04-7.00 (m, 1H), 6.80 (dd, J = 8.0, 1.3 Hz,1H), 6.69 (dd, J = 8.1, 1.4 Hz, 1H), 1.45 (s, 9H) 183 1H NMR (400 MHz,DMSO-d6) δ 12.42 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H),8.06 (d, J = 2.1 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52 (m, 1H), 7.38(dd, J = 8.2, 2.1 Hz, 1H), 7.08 (d, J = 8.3 Hz, 1H), 3.66-3.63 (m, 2H),2.70 (t, J = 6.5 Hz, 2H), 1.86-1.80 (m, 2H), 1.51 (s, 9H) 186 H NMR (400MHz, DMSO-d6) δ 12.93 (s, 1H), 12.47 (s, 1H), 10.72 (s, 1H), 8.89 (s,1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.82 (t,J = 8.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H),7.50 (d, J = 8.4 Hz, 1H), 7.05-7.02 (m, 2H), 3.19 (quintet, J = 8.2 Hz,1H), 2.08 (m, 2H), 1.82-1.60 (m, 6H) 187 1H NMR (400 MHz, DMSO-d6) δ12.63 (s, 1H), 8.91 (s, 1H), 8.87-8.87 (m, 1H), 8.36 (dd, J = 8.2, 1.2Hz, 1H), 7.85-7.75 (m, 3H), 7.64-7.53 (m, 3H), 6.71 (dd, J = 3.7, 0.5Hz, 1H), 2.67 (s, 3H) 188 H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H),12.73 (d, J = 6.6 Hz, 1H), 11.39 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.61(s, 1H), 8.33 (d, J = 6.8 Hz, 1H), 8.23 (s, 1H), 7.80 (t, J = 8.4 Hz,1H), 7.73 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 8.1 Hz, 1H), 7.43 (m, 1H),6.54 (m, 1H), 4.38 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H) 204 HNMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 12.37 (s, 1H), 8.87 (d, J = 1.2Hz, 1H), 8.32 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.2, 7.0 Hz, 1H), 7.75(d, J = 8.3 Hz, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.32-7.28 (m, 2H), 7.05(d, J = 8.4 Hz, 1H), 4.16 (t, J = 4.9 Hz, 2H), 1.78 (t, J = 4.9 Hz, 2H),1.29 (s, 6H), 207 H NMR (400 MHz, DMSO-d6) δ 12.92 (br s, 1H), 12.50 (s,1H), 10.95 (s, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H), 8.17(d, J = 1.5 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H),7.55 (t, J = 8.1 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.21 (d, J = 2.3 Hz,1H), 7.06 (dd, J = 8.5, 1.8 Hz, 1H), 4.09 (q, J = 7.1 Hz, 2H), 3.72 (s,2H), 1.20 (t, J = 7.1 Hz, 3H) 215 H NMR (400 MHz, DMSO-d6) δ 12.97 (s,1H), 12.50 (s, 1H), 8.89 (s, 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 7.83(t, J = 8.3 Hz, 1H), 7.75 (m, 3H), 7.55 (t, J = 8.1 Hz, 1H), 7.37 (t, J= 7.9 Hz, 2H), 7.10 (t, J = 6.8 Hz, 1H) 220 H NMR (400 MHz, DMSO-d6) δ12.99 (d, J = 6.6 Hz, 1H), 12.07 (s, 1H), 8.93 (d, J = 6.8 Hz, 1H), 8.35(d, J = 7.1 Hz, 1H), 8.27 (s, 1H), 8.12 (s, 1H), 7.85-7.77 (m, 2H), 7.54(td, J = 7.5, 1.2 Hz, 1H), 6.81 (s, 1H), 1.37 (d, J = 3.9 Hz, 9H), 1.32(d, J = 17.1 Hz, 9H) 225 1H NMR (CD3OD, 300 MHz) δ 8.79 (s, 1H), 8.37(d, J = 7.9 Hz, 1H), 7.75 (m, 2H), 7.61 (d, J = 8.3 Hz, 1H), 7.5 (m,2H), 7.29 (d, J = 8.3 Hz, 1H), 4.21 (q, J = 7.2, 2H), 3.17 (m, 1H), 1.32(t, J = 7.2 Hz, 3H), 1.24 (d, J = 6.9 Hz, 6H). 232 1H-NMR (CD3OD, 300MHz) δ 8.87 (s, 1H), 8.45 (d, J = 8.25, 1H), 8.27 (m, 1H), 7.83 (t, J =6.88, 1H), 7.67 (d, J = 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.39 (d, J =6.05, 1H), 7.18 (d, J = 8.5, 1H), 2.77 (t, J = 6.87, 2H), 2.03 (s, 3H),1.7 (q, 2H), 1.04 (t, J = 7.42, 3H) 233 1H NMR (400 MHz, DMSO-d6) δ12.75 (d, J = 13.6 Hz, 1H), 8.87 (s, 1H), 8.32-8.28 (m, 2H), 7.76-7.70(m, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.49-7.45 (m, 1H), 7.18 (d, J = 8.4Hz, 1H), 4.11 (t, J = 8.3 Hz, 2H), 3.10 (t, J = 7.7 Hz, 2H), 2.18 (s,3H) 234 1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 11.50 (s, 1H), 8.90(s, 1H), 8.36-8.34 (m, 2H), 7.97 (s, 1H), 7.85-7.81 (m, 1H), 7.77-7.75(m, 1H), 7.56-7.50 (m, 2H), 6.59-6.58 (m, 1H) 235 H NMR (400 MHz,DMSO-d6) δ 13.09 (d, J = 6.5 Hz, 1H), 12.75 (s, 1H), 9.04 (s, 1H), 8.92(d, J = 6.8 Hz, 1H), 8.42 (d, J = 7.1 Hz, 1H), 8.34 (d, J = 6.9 Hz, 1H),7.85 (t, J = 8.4 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.63-7.56 (m, 2H),3.15 (m, 1H), 1.29 (d, J = 6.9 Hz, 6H) 238 H NMR (400 MHz, DMSO-d6) δ12.93 (d, J = 6.4 Hz, 1H), 12.29 (s, 1H), 8.85 (d, J = 6.7 Hz, 1H), 8.32(d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.9 Hz, 1H),7.54 (t, J = 8.1 Hz, 1H), 7.17 (m, 2H), 6.94 (m, 1H), 3.79 (m, 2H),3.21-2.96 (m, 4H), 1.91-1.76 (m, 4H), 1.52 (m, 2H), 1.43 (s, 9H) 242 HNMR (400 MHz, DMSO-d6) δ 12.95 (d, J = 6.6 Hz, 1H), 12.65 (s, 1H), 8.87(d, J = 6.8 Hz, 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 8.17 (s, 1H), 7.83(t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H),7.37 (s, 1H), 5.60 (s, 2H) 243 1H-NMR (CD3OD, 300 MHz) δ 8.87 (s, 1H),8.45 (d, J = 8.25, 1H), 8.27 (m, 1H), 7.83 (t, J = 6.88, 1H), 7.67 (d, J= 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.39 (d, J = 6.05, 1H), 7.18 (d, J= 8.5, 1H), 2.77 (t, J = 6.87, 2H), 2.03 (s, 3H), 1.7 (q, 2H), 1.04 (t,J = 7.42, 3H) NMR Shows regio isomer 244 H NMR (400 MHz, DMSO-d6) δ12.89 (s, 1H), 12.42 (s, 1H), 10.63 (s, 1H), 8.88 (d, J = 6.7 Hz, 1H),8.35 (d, J = 8.2 Hz, 1H), 8.03 (d, J = 1.6 Hz, 1H), 7.82 (t, J = 8.3 Hz,1H), 7.76 (d, J = 7.7 Hz, 1H), 7.54 (t, J = 8.1 Hz, 1H), 7.29 (d, J =8.3 Hz, 1H), 7.02 (dd, J = 8.4, 1.8 Hz, 1H), 2.69 (t, J = 5.3 Hz, 2H),2.61 (t, J = 5.0 Hz, 2H), 1.82 (m, 4H) 248 H NMR (400 MHz, DMSO-d6) δ12.95 (d, J = 6.6 Hz, 1H), 12.42 (s, 1H), 9.30 (s, 1H), 8.86 (d, J = 6.8Hz, 1H), 8.33 (dd, J = 8.1, 1.3 Hz, 1H), 7.85-7.81 (m, 2H), 7.76 (d, J =7.8 Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.49 (dd, J = 8.2, 2.2 Hz, 1H),7.18 (d, J = 8.3 Hz, 1H), 2.18 (s, 3H), 2.08 (s, 3H) 259 H NMR (400 MHz,DMSO-d6) δ 0.86 (t, J = 7.4 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.67 (m,2H), 2.88 (m, 1H), 7.03 (m, 2H), 7.53 (m, 2H), 7.80 (m, 2H), 8.13 (s,1H), 8.35 (d, J = 8.2 Hz, 1H), 8.89 (s, 1H), 10.75 (s, 1H), 12.45 (s,1H), 12.84 (s, 1H) 260 H NMR (400 MHz, DMSO-d6) δ 13.23 (d, J = 6.6 Hz,1H), 12.20 (s, 1H), 10.22 (br s, 2H), 8.88 (d, J = 6.8 Hz, 1H), 8.34 (d,J = 7.8 Hz, 1H), 7.86-7.80 (m, 3H), 7.56-7.52 (m, 2H), 7.15 (dd, J =8.5, 2.4 Hz, 1H), 1.46 (s, 9H) 261 1H-NMR (d6-DMSO, 300 MHz) δ 11.99 (s,1H, NH), 8.76 (s, J = 6.6 Hz, 1H), 8.26 (d, J = 6.2 Hz, 1H), 8.09 (d, J= 7.9 Hz, 1H), 7.72-7.63 (m, 2H), 7.44-7.09 (m, 7H), 2.46 (s, 3H), 2.25(s, 3H). 262 1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 12.53 (s, 1H),10.62 (s, 1H), 8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.2 Hz, 1H), 7.85-7.75(m, 2H), 7.57-7.50 (m, 2H), 7.34-7.28 (m, 2H), 3.46 (s, 2H) 266 H NMR(400 MHz, DMSO-d6) δ 12.94 (d, J = 6.6 Hz, 1H), 12.57 (s, 1H), 10.37 (s,1H), 8.88 (d, J = 6.8 Hz, 1H), 8.34-8.32 (m, 1H), 7.99 (s, 1H),7.85-7.81 (m, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.56-7.52 (m, 1H), 7.38 (s,1H), 1.37 (s, 9H) 268 H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 12.62(s, 1H), 8.91 (s, 1H), 8.34 (dd, J = 8.1, 1.1 Hz, 1H), 8.22 (d, J = 2.4Hz, 1H), 8.14 (dd, J = 8.8, 2.4 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.77(d, J = 7.8 Hz, 1H), 7.65-7.54 (m, 4H), 1.52 (s, 9H) 271 H NMR (400 MHz,DMSO-d6) δ 1.38 (s, 9H), 4.01 (s, 2H), 7.35 (s, 2H), 7.55 (m, 1H), 7.65(s, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.83 (m, 1H), 8.33 (d, J = 7.6 Hz,1H), 8.86 (d, J = 6.8 Hz, 1H), 12.49 (s, 1H), 13.13 (s, 1H) 272 1H-NMR(d6-Acetone, 300 MHz) δ 8.92 (d, J = 6.6 Hz, 1H), 8.39 (d, J = 7.8 Hz,1H), 7.94 (s, 1H), 7.79 (s, 1H), 7.77 (s, 2H), 7.53 (m, 1H), 7.36 (s,1H), 3.94-3.88 (m, 5H), 3.64-3.59 (m, 3H), 3.30 (m, 4H). 274 H NMR (400MHz, DMSO-d6) δ 13.21 (d, J = 6.6 Hz, 1H), 11.66 (s, 1H), 10.95 (s, 1H),9.00 (d, J = 6.5 Hz, 1H), 8.65 (d, J = 2.1 Hz, 1H), 8.18 (dd, J = 8.7,2.2 Hz, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.57 (m, 2H), 7.31 (t, J = 2.7Hz, 1H), 6.40 (t, J = 2.0 Hz, 1H), 3.19 (m, 4H), 1.67 (m, 4H), 1.46 (s,9H) 275 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 9.47 (s, 1H), 9.20 (s,1H), 8.43 (d, J = 7.9 Hz, 1H), 7.79 (t, J = 2.0 Hz, 2H), 7.56 (m, 1H),7.38-7.26 (m, 6H), 7.11 (d, J = 8.4 Hz, 1H), 6.99 (dd, J = 8.4, 2.1 Hz,1H), 5.85 (s, 2H), 1.35 (s, 9H) 282 1H NMR (CD3OD, 300 MHz) δ 8.90 (s,1H), 8.51 (s, 1H), 8.44 (d, J = 7.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H),7.69 (d, J = 8.5 Hz, 1H), 7.56 (t, J = 7.7 Hz, 2H), 7.42 (d, J = 7.9 Hz,1H), 7.07 (d, J = 5.8 Hz, 1H), 2.93 (q, J = 7.4 Hz, 2H), 1.36 (t, J =7.5 Hz, 3H). 283 1H-NMR (CDCl3, 300 MHz) δ 8.82 (d, J = 6.6 Hz, 1H),8.29 (d, J = 6.2 Hz, 1H), 8.06 (d, J = 7.9 Hz, 1H), 7.43-7.24 (m, 6H),7.02 (m, 2H), 6.87-6.81 (dd, 2H), 3.76 (s, 3H). 287 H NMR (400 MHz,DMSO-d6) δ 13.51 (s, 1H), 13.28 (d, J = 6.6 Hz, 1H), 11.72 (d, J = 2.2Hz, 1H), 9.42 (s, 1H), 8.87 (d, J = 6.9 Hz, 1H), 8.04 (d, J = 7.4 Hz,1H), 7.67 (t, J = 8.2 Hz, 1H), 7.17 (dd, J = 8.3, 0.8 Hz, 1H), 7.01 (d,J = 13.7 Hz, 1H), 6.81 (dd, J = 8.1, 0.8 Hz, 1H), 2.10 (m, 2H),1.63-1.34 (m, 8H), 1.26 (s, 3H) 288 H NMR (400 MHz, DMSO-d6) δ 13.16 (s,1H), 12.85 (s, 1H), 8.98 (s, 1H), 8.43 (dd, J = 8.1, 1.1 Hz, 1H), 8.34(dd, J = 10.3, 3.1 Hz, 1H), 7.93 (t, J = 8.4 Hz, 1H), 7.86 (d, J = 7.7Hz, 1H), 7.66 (t, J = 8.1 Hz, 1H), 7.03 (dd, J = 10.7, 3.2 Hz, 1H), 4.06(s, 3H), 1.42 (s, 9H) 295 H NMR (400 MHz, DMSO-d6) δ 1.98 (m, 4H), 3.15(m, 4H), 7.04 (m, 2H), 7.17 (d, J = 7.8 Hz, 1H), 7.52 (m, 1H), 7.74 (d,J = 7.8 Hz, 1H), 7.81 (m, 1H), 8.19 (dd, J = 7.9, 1.4 Hz, 1H), 8.33 (d,J = 8.1 Hz, 1H), 8.88 (d, J = 6.7 Hz, 1H), 12.19 (s, 1H), 12.87 (s, 1H)299 1H NMR (400 MHz, DMSO-d6) δ 12.93-12.88 (m, 1H), 12.18 (s, 1H), 8.83(d, J = 6.8 Hz, 1H), 8.38-8.31 (m, 1H), 7.85-7.67 (m, 2H), 7.57-7.51 (m,1H), 6.94 (s, 1H), 6.81-6.74 (m, 2H), 3.19-3.16 (m, 2H), 2.68-2.61 (m,2H), 1.80-1.79 (m, 2H) 300 H NMR (400 MHz, DMSO-d6) δ 13.23 (d, J = 6.6Hz, 1H), 12.59 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 7.7 Hz,1H), 7.86-7.79 (m, 3H), 7.58-7.42 (m, 3H), 3.38 (m, 2H), 1.88 (m, 2H),1.30 (s, 6H) 303 H NMR (400 MHz, DMSO-d6) δ 12.96 (d, J = 6.5 Hz, 1H),12.47 (s, 0.4H), 12.43 (s, 0.6H), 8.87 (dd, J = 6.7, 2.3 Hz, 1H), 8.33(d, J = 8.1 Hz, 1H), 7.82 (t, J = 8.2 Hz, 1H), 7.75 (d, J = 8.3 Hz, 1H),7.62-7.52 (m, 3H), 7.17 (d, J = 8.3 Hz, 1H), 4.66 (s, 0.8H), 4.60 (s,1.2H), 3.66 (t, J = 5.9 Hz, 2H), 2.83 (t, J = 5.8 Hz, 1.2H), 2.72 (t, J= 5.9 Hz, 0.8H), 2.09 (m, 3H) 304 1H NMR (300 MHz, DMSO-d6) δ 11.70 (s,1H), 8.74 (s, 1H), 8.15 (s, 1H), 8.07 (m, 1H), 7.72 (m, 1H), 7.63 (d, J= 8.4 Hz, 1H), 7.45-7.31 (m, 3H), 7.15-6.95 (m, 5H), 4.17 (d, J = 6.0Hz, 2H), 4.02 (q, J = 6.9 Hz, 2H), 1.40 (s, 9H), 1.09 (t, J = 6.9 Hz,3H). 307 1H-NMR (CDCl3, 300 MHz) δ 8.81 (d, J = 6.6 Hz, 1H), 8.30 (d, J= 6.2 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.44-7.26 (m, 9H), 6.79 (d, J =7.5 Hz, 1H). 318 1H-NMR (d6-Acetone, 300 MHz) δ 8.92 (bs, 1H), 8.40 (d,J = 8.1 Hz, 1H), 8.05 (bs, 1H), 7.94 (bs, 1H), 7.78 (bs, 2H), 7.52 (m,1H), 7.36 (bs, 1H), 3.97 (t, J = 7.2 Hz, 2H), 3.66 (t, J = 8 Hz, 2H),3.31-3.24 (m, 6H), 1.36-1.31 (m, 4H). 320 ¹H NMR (400 MHz, DMSO-d6) δ12.90 (s, 1H), 12.44 (s, 1H), 10.86 (s, 1H), 8.90 (s, 1H), 8.35 (dd, J =8.2, 1.0 Hz, 1H), 8.12 (t, J = 0.8 Hz, 1H), 7.84-7.75 (m, 2H), 7.56-7.52(m, 1H), 7.37 (d, J = 8.3 Hz, 1H), 6.99 (dd, J = 8.4, 1.9 Hz, 1H),6.08-6.07 (m, 1H), 1.35 (s, 9H) 321 H NMR (400 MHz, DMSO-d6) δ 2.93 (m,4H), 3.72 (m, 4H), 7.10 (m, 2H), 7.27 (d, J = 7.8 Hz, 1H), 7.51 (m, 6H),7.74 (d, J = 8.2 Hz, 1H), 7.81 (m, 1H), 8.40 (d, J = 8.1 Hz, 1H), 8.58(d, J = 8.0 Hz, 1H), 8.88 (d, J = 6.7 Hz, 1H), 12.69 (s, 1H), 12.86 (s,1H) 323 H NMR (400 MHz, DMSO-d6) δ 12.94 (br s, 1H), 12.44 (s, 1H), 8.89(s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76(d, J = 7.7 Hz, 1H), 7.67 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 8.1 Hz, 1H),7.35 (d, J = 8.7 Hz, 2H), 7.02 (t, J = 6.3 Hz, 1H), 3.50 (s, 3H), 3.17(d, J = 6.2 Hz, 2H), 1.23 (s, 6H) 334 H NMR (400 MHz, DMSO-d6) δ 13.02(br s, 1H), 12.46 (s, 1H), 8.89 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H),7.89 (s, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.55(t, J = 8.1 Hz, 1H), 7.44 (m, 1H), 7.37 (d, J = 8.6 Hz, 1H), 3.85 (m,2H), 3.72 (t, J = 6.0 Hz, 2H), 3.18-3.14 (m, 2H), 2.23 (s, 3H), 1.93 (t,J = 5.7 Hz, 2H), 1.79 (m, 2H), 1.53 (m, 2H), 1.43 (s, 9H) 337 H NMR (400MHz, DMSO-d6) δ 12.19 (s, 1H), 9.35 (s, 1H), 8.22 (dd, J = 8.1, 1.1 Hz,1H), 8.08 (s, 1H), 7.74-7.70 (m, 1H), 7.65 (d, J = 7.8 Hz, 1H),7.44-7.40 (m, 1H), 7.23 (s, 1H), 3.31 (s, 3H), 1.37 (s, 9H), 1.36 (s,9H) 351 1H NMR (400 MHz, DMSO-d6) δ 12.92 (s, 1H), 12.34 (s, 1H), 10.96(s, 1H), 8.91 (s, 1H), 8.48 (s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.84-7.76(m, 2H), 7.53 (t, J = 7.4 Hz, 1H), 7.39 (s, 1H), 7.26 (t, J = 2.6 Hz,1H), 6.34 (s, 1H), 2.89-2.84 (m, 2H), 1.29 (t, J = 7.4 Hz, 3H) 353 1HNMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 9.30 (s, 1H), 8.88 (s, 1H), 8.34(dd, J = 8.2, 1.1 Hz, 1H), 7.84-7.71 (m, 3H), 7.55-7.50 (m, 1H),7.28-7.26 (m, 1H), 7.20-7.17 (m, 1H), 1.47 (s, 9H), 1.38 (s, 9H) 3561H-NMR (CD3OD, 300 MHz) δ 8.89 (s, 1H), 8.59 (s, 1H), 8.45 (d, J = 8.3Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.57 (t, J= 7.9 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.17 (d, J = 6.0 Hz, 1H), 3.09(s, 3H, NMe), 2.91 (t, J = 7.4 Hz, 2H), 1.76 (m, 2H), 1.09 (t, J = 7.4Hz, 3H). 357 H NMR (400 MHz, DMSO-d6) δ 12.91 (d, J = 6.6 Hz, 1H), 12.45(s, 1H), 10.73 (d, J = 1.9 Hz, 1H), 8.89 (d, J = 6.7 Hz, 1H), 8.35 (dd,J = 8.1, 1.3 Hz, 1H), 8.13 (d, J = 1.6 Hz, 1H), 7.83 (t, J = 8.3 Hz,1H), 7.76 (d, J = 7.7 Hz, 1H), 7.57-7.51 (m, 2H), 7.06-7.02 (m, 2H),3.12 (septet, J = 6.6 Hz, 1H), 1.31 (d, J = 6.9 Hz, 6H) 363 1H-NMR(CDCl3, 300 MHz) δ 8.86 (d, J = 6.6 Hz, 1H), 8.24 (d, J = 6.2 Hz, 1H),8.14 (d, J = 7.9 Hz, 1H), 7.43-7.16 (m, 5H), 7.02-6.92 (m, 2H), 6.83 (d,J = 7.9 Hz, 2H), 3.87 (s, 3H). 368 H NMR (400 MHz, DMSO-d6) δ 12.97 (d,J = 6.6 Hz, 1H), 12.36 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.33 (dd, J =8.1, 1.0 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H),7.62 (s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.25 (dd, J = 8.7, 2.2 Hz, 1H),7.01 (d, J = 8.8 Hz, 1H), 3.98 (t, J = 6.5 Hz, 2H), 1.78 (sextet, J =6.9 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H) 375 H NMR (400 MHz, DMSO-d6) δ12.93 (d, J = 6.2 Hz, 1H), 12.35 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.33(d, J = 6.9 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.8 Hz, 1H),7.54 (t, J = 8.1 Hz, 1H), 7.47-7.43 (m, 2H), 7.04 (d, J = 8.2 Hz, 1H),2.71 (m, 4H), 1.75 (m, 4H) 378 H NMR (400 MHz, DMSO-d6) δ 12.98 (d, J =6.6 Hz, 1H), 12.39 (s, 1H), 8.86 (d, J = 6.7 Hz, 1H), 8.33 (dd, J = 8.1,1.2 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.77 (d, J = 7.7 Hz, 1H), 7.69(s, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.31 (dd, J = 8.8, 2.4 Hz, 1H), 7.06(d, J = 8.8 Hz, 1H), 3.85 (s, 3H) 379 1H NMR (300 MHz, DMSO-d6) δ 12.79(s, 1H), 10.30 (s, 1H), 8.85 (s, 1H), 8.32 (d, J = 7.8 Hz, 1H), 8.06 (s,1H), 7.93 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H), 7.74 (d, J = 6.9 Hz, 1H),7.73 (s, 1H), 7.53 (t, J = 6.9 Hz, 1H), 2.09 (s, 3H). 381 H NMR (400MHz, DMSO-d6) δ 12.78 (br s, 1H), 11.82 (s, 1H), 10.86 (s, 1H), 8.83 (s,1H), 8.28 (dd, J = 8.1, 1.0 Hz, 1H), 7.75 (t, J = 8.3 Hz, 1H), 7.69 (d,J = 7.7 Hz, 1H),, 7.49-7.43 (m, 3H), 7.23 (m, 1H), 6.32 (m, 1H), 1.39(s, 9H) 382 1H NMR (CD3OD, 300 MHz) δ 8.83 (s, 1H), 8.40 (d, J = 7.4 Hz,1H), 7.81-7.25 (m, 2H), 7.65 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.2, 1H),7.24 (d, J = 8.3, 1H), 2.58 (t, J = 7.7 Hz, 2H), 2.17 (s, 3H), 1.60 (m,2H), 0.97 (t, J = 7.4 Hz, 3H). 383 H NMR (400 MHz, DMSO-d6) δ 1.27 (t, J= 7.5 Hz, 3H), 2.70 (q, J = 7.7 Hz, 2H), 7.05 (m, 2H), 7.47 (d, J = 8.4Hz, 1H), 7.55 (t, J = 8.1 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.83 (t, J= 8.3 Hz, 1H), 8.13 (s, 1H), 8.35 (d, J = 6.9 Hz, 1H), 8.89 (d, J = 6.7Hz, 1H), 10.73 (s, 1H), 12.46 (s, 1H), 12.91 (s, 1H) 386 H NMR (400 MHz,DMSO-d6) δ 13.18 (d, J = 6.8 Hz, 1H), 12.72 (s, 1H), 8.88 (d, J = 6.8Hz, 1H), 8.34 (d, J = 8.1 Hz, 1H), 8.09 (s, 1H), 7.86-7.79 (m, 2H),7.58-7.50 (m, 2H), 7.43 (d, J = 8.2 Hz, 1H), 3.51 (s, 2H), 1.36 (s, 6H)393 1H NMR (300 MHz, MeOH) δ 8.78 (s, 1H), 8.45 (d, J = 2.1 Hz, 1H),8.16 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 6.9, Hz, 1H), 7.56 (d, J = 8.7Hz, 1H), 7.39 (m, 3H), 7.18 (m, 2H), 7.06 (m, 2H), 4.02 (m, 2H), 1.13(t, J = 6.9 Hz, 3H); 399 1H-NMR (CD3OD, 300 MHz) δ 8.91 (s, 1H), 8.51(s, 1H), 8.42 (d, J = 8.3 Hz, 1H), 7.84 (t, J = 7.2 Hz, 1H), 7.67 (d, J= 9.0 Hz, 1H), 7.56 (t, J = 7.9 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.24(d, J = 6.0 Hz, 1H), 3.48 (m, 1H), 3.09 (s, 3H, NMe), 1.39 (d, J = 6.8Hz, 6H). 412 H NMR (400 MHz, DMSO-d6) δ 12.81-12.79 (m, 2H), 10.96 (s,1H), 8.87 (d, J = 6.7 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.99 (d, J =8.6 Hz, 1H), 7.83-7.73 (m, 3H), 7.53 (t, J = 8.1 Hz, 1H), 7.36 (m, 1H),6.52 (m, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H) 415 HNMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 9.46 (s, 1H), 8.99 (s, 1H),8.43-8.41 (m, 1H), 7.94-7.88 (m, 2H),, 7.65-7.61 (m, 1H), 7.38 (d, J =2.1 Hz, 1H), 7.10 (d, J = 8.4 Hz, 1H), 6.96 (dd, 1H), 4.08 (s, 3H), 1.35(s, 9H) 420 H NMR (400 MHz, DMSO-d6) δ 12.91 (bs, 1H), 12.51 (s, 1H),8.89 (s, 1H), 8.33 (dd, J = 8, 1 Hz, 2H), 7.82 (ddd, J = 8, 8, 1 Hz,1H), 7.75 (dd, J = 8, 1 Hz, 1H), 7.70 (d, J = 9 Hz, 2H), 7.54 (ddd, J =8, 8, 1 Hz, 1H), 4.09 (q, J = 7 Hz, 2H), 1.51 (s, 6H), 1.13 (t, J = 7Hz, 3H). 423 H NMR (400 MHz, DMSO-d6) δ 12.91 (br s, 1H), 12.48 (s, 1H),10.81 (d, J = 1.8 Hz, 1H), 8.89 (s, 1H), 8.35 (dd, J = 8.2, 1.1 Hz, 1H),8.14 (d, J = 1.6 Hz, 1H), 7.82 (t, J = 7.6 Hz, 1H), 7.76 (d, J = 7.8 Hz,1H), 7.56-7.48 (m, 2H), 7.11 (d, J = 2.2 Hz, 1H), 7.05 (dd, J = 8.5, 1.8Hz, 1H), 3.62 (t, J = 7.3 Hz, 2H), 3.48 (q, J = 7.0 Hz, 2H), 2.91 (t, J= 7.3 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H) 425 1H-NMR (DMSO d6, 300 MHz) δ8.84 (s, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.78-7.70 (m, 2H), 7.61 (d, J =8.4 Hz, 2H), 7.50 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 2H), 2.85(h, J = 6.9 Hz, 1H), 1.19 (d, J = 6.9 Hz, 6H). 427 H NMR (400 MHz,DMSO-d6) δ 1.45 (s, 9H), 2.84 (t, J = 5.9 Hz, 2H), 3.69 (m, 2H), 4.54(s, 1H), 6.94 (d, J = 7.5 Hz, 1H), 7.22 (t, J = 7.9 Hz, 1H), 7.55 (m,1H), 7.77 (d, J = 7.7 Hz, 1H), 7.83 (m, 1H), 8.24 (d, J = 8.0 Hz, 1H),8.37 (d, J = 9.2 Hz, 1H), 8.91 (s, 1H), 12.36 (s, 1H), 12.99 (s, 1H) 4281H NMR (300 MHz, CD3OD) δ 12.30 (s, 1H), 8.83 (s, 1H), 8.38 (d, J = 7.4Hz, 1H), 7.78 (app dt, J = 1.1, 7.1 Hz, 1H), 7.64 (d, J = 8..3 Hz, 1H),7.53 (app t, J = 7.5 Hz, 1H), 7.21 (br d, J = 0.9 Hz, 1H), 7.15 (d, J =8.4 Hz, 1H), 6.98 (dd, J = 2.1, 8.4 Hz, 1H), 1.38 (s, 9H) 429 H NMR (400MHz, DMSO-d6) δ 13.13 (d, J = 6.8 Hz, 1H), 12.63 (s, 1H), 8.86 (d, J =6.8 Hz, 1H), 8.33 (d, J = 7.0 Hz, 1H), 7.84 (t, J = 8.3 Hz, 1H), 7.78(d, J = 7.6 Hz, 1H), 7.56 (t, J = 8.1 Hz, 1H), 7.51 (s, 1H), 7.30 (s,1H), 6.77 (s, 1H) 433 H NMR (400 MHz, DMSO-d6) δ 12.87 (br s, 1H), 11.82(s, 1H), 9.20 (s, 1H), 8.87 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H),7.81 (t, J = 8.3 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H), 7.52 (t, J = 8.1 Hz,1H), 7.17 (s, 1H), 7.10 (s, 1H), 1.38 (s, 9H), 1.36 (s, 9H) 438 H NMR(400 MHz, DMSO-d6) δ 12.97 (d, J = 6.6 Hz, 1H), 12.08 (s, 1H), 8.90 (d,J = 6.8 Hz, 1H), 8.35-8.34 (m, 1H), 8.03 (s, 1H), 7.85-7.81 (m, 1H),7.77-7.71 (m, 1H), 7.58-7.44 (m, 2H), 1.46 (s, 9H), 1.42 (s, 9H) 4411H-NMR (d6-Acetone, 300 MHz) δ 11.90 (br s, 1H), 8.93 (br s, 1H), 8.42(d, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.92 (s, 1H), 7.79 (m, 2H), 7.57 (m,1H), 7.36 (s, 1H), 3.13 (s, 3H). 444 H NMR (400 MHz, DMSO-d6) δ 12.56(s, 1H), 12.17 (br d, J = 6 Hz, 1H), 8.89 (d, J = 6 Hz, 1H), 8.42 (dd, J= 9, 2 Hz, 1H), 7.77 (d, J = 2 Hz, 1H), 7.68 (dd, J = 9, 2 Hz, 1H), 7.60(ddd, J = 9, 9, 2 Hz, 1H), 7.46-7.40 (m, 3H), 3.47 (s, 3H), 1.35 (s,9H). 448 H NMR (400 MHz, DMSO-d6) δ 12.96 (br s, 1H), 12.42 (s, 1H),8.88 (s, 1H), 8.33 (dd, J = 8.2, 1.1 Hz, 1H), 7.82 (t, J = 8.3 Hz, 1H),7.75 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.54 (t, J = 8.1 Hz,1H), 7.39 (d, J = 8.7 Hz, 2H), 1.29 (s, 9H) 453 H NMR (400 MHz, DMSO-d6)δ 12.95 (d, J = 6.5 Hz, 1H), 12.38 (s, 1H), 8.86 (d, J = 6.8 Hz, 1H),8.33 (d, J = 8.1 Hz, 1H), 7.83 (t, J = 8.3 Hz, 1H), 7.76 (d, J = 7.8 Hz,1H), 7.54 (t, J = 8.1 Hz, 1H), 7.28 (d, J = 2.4 Hz, 1H), 7.15 (d, J =8.6 Hz, 1H), 6.94 (dd, J = 8.6, 2.4 Hz, 1H) 458 H NMR (400 MHz, DMSO-d6)δ 12.97 (d, J = 7.1 Hz, 1H), 12.39 (s, 1H), 8.88 (d, J = 6.8 Hz, 1H),8.33 (d, J = 7.9 Hz, 1H), 7.83 (t, J = 7.6 Hz, 1H), 7.75 (d, J = 8.2 Hz,1H), 7.55 (t, J = 7.6 Hz, 1H), 7.47 (s, 1H), 7.17 (s, 2H), 4.04 (t, J =5.0 Hz, 2H), 3.82 (t, J = 5.0 Hz, 2H), 1.36 (s, 9H) 461 1H-NMR (d6-DMSO,300 MHz) δ 11.97 (s, 1H), 8.7 (s, 1H), 8.30 (d, J = 7.7 Hz, 1H), 8.07(d, J = 7.7 Hz, 1H), 7.726-7.699 (m, 2H), 7.446-7.357 (m, 6H),7.236-7.178 (m, 2H). 13C-NMR (d6-DMSO, 75 MHz) d 176.3, 163.7, 144.6,139.6, 138.9, 136.3, 134.0, 133.4, 131.0, 129.8, 129.2, 128.4, 128.1,126.4, 126.0, 125.6, 124.7, 123.6, 119.6, 111.2. 463 1H-NMR (DMSO d6,300 MHz) δ 8.83 (s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.78-7.70 (m, 2H),7.61 (d, J = 7.8 Hz, 2H), 7.51 (t, 1H), 7.17 (d, J = 8.1 Hz, 2H), 2.57(q, J = 7.5 Hz, 2H), 1.17 (t, J = 7.5 Hz, 1H), 0.92 (t, J = 7.8 Hz, 3H).464 H NMR (400 MHz, DMSO-d6) δ 1.37 (s, 9H), 1.38 (s, 9H), 6.80 (dd, J =8.1, 0.9 Hz, 1H), 7.15 (m, 3H), 7.66 (t, J = 8.2 Hz, 1H), 8.87 (d, J =6.9 Hz, 1H), 9.24 (s, 1H), 11.07 (s, 1H), 13.23 (d, J = 6.5 Hz, 1H),13.65 (s, 1H) 465 H NMR (400 MHz, DMSO-d6) δ 12.94 (d, J = 6.0 Hz, 1H),12.40 (s, 1H), 8.87 (d, J = 6.8 Hz, 1H), 8.33 (d, J = 8.2 Hz, 1H),7.84-7.75 (m, 3H), 7.57-7.43 (m, 2H), 7.31 (d, J = 8.6 Hz, 1H), 4.40 (d,J = 5.8 Hz, 2H), 1.44 (s, 9H), 1.38 (s, 9H) 471 1H-NMR (CD3OD, 300 MHz)δ 8.87 (s, 1H), 8.44 (d, J = 8.25, 1H), 8.18 (m, 1H), 7.79 (t, J = 6.88,1H), 7.67 (d, J = 8.25, 1H), 7.54 (t, J = 7.15, 1H), 7.23 (d, J = 6.05,1H), 7.16 (d, J = 8.5, 1H), 3.73 (s, 3H), 2.75 (t, J = 6.87, 2H), 1.7(q, 2H), 1.03 (t, J = 7.42, 3H) 476 H NMR (400 MHz, DMSO-d6) δ 13.00 (d,J = 6.4 Hz, 1H), 12.91 (s, 1H), 10.72 (s, 1H), 8.89 (d, J = 6.8 Hz, 1H),8.34 (d, J = 8.2 Hz, 1H), 8.16 (s, 1H), 7.85-7.75 (m, 2H), 7.56-7.54 (m,1H), 7.44 (s, 1H), 1.35 (s, 9H) 478 H NMR (400 MHz, DMSO-d6) δ 1.40 (s,9H), 6.98 (d, J = 2.4 Hz, 1H), 7.04 (dd, J = 8.6, 1.9 Hz, 1H), 7.55 (t,J = 8.1 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H),7.83 (t, J = 8.3 Hz, 1H), 8.13 (d, J = 1.7 Hz, 1H), 8.35 (d, J = 8.1 Hz,1H), 8.89 (d, J = 6.7 Hz, 1H), 10.74 (s, 1H), 12.44 (s, 1H), 12.91 (s,1H) 484 1H NMR (300 MHz, DMSO-d6) δ 12.90 (d, J = 6.3 Hz, 1H), 12.21 (s,1H), 8.85 (d, J = 6.8 Hz, 1H), 8.31 (d, J = 8.0 Hz, 1H), 7.79 (app dt, J= 12, 8.0 Hz, 1H), 7.72 (d, J = 8.3 Hz, 1H), 7.52 (dd, J = 6.9, 8.1 Hz,1H), 7.05 (d, J = 8.3 Hz, 1H), 6.94 (s with fine str, 1H), 1H), 6.90 (dwith fine str, J = 8.4 Hz, 1H), 2.81 (s, 3H), 1.34 (s, 9H) 485 1H NMR(300 MHz, CDCl₃) δ 13.13 (br s, 1H), 12.78 (s, 1H), 8.91 (br s, 1H),8.42 (br s, 1H), 8.37 (d, J = 8.1 Hz, 1H), 7.72-7.58 (m, 2H), 7.47-7.31(m, 3H), 3.34 (s, 6H), 1.46 (s, 9H)

B) Assays for Detecting and Measuring ΔF508-CFTR Correction Propertiesof Compounds

I) Membrane Potential Optical Methods for Assaying ΔF508-CFTR ModulationProperties of Compounds

The optical membrane potential assay utilized voltage-sensitive FRETsensors described by Gonzalez and Tsien (See, Gonzalez, J. E. and R. Y.Tsien (1995) “Voltage sensing by fluorescence resonance energy transferin single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y.Tsien (1997) “Improved indicators of cell membrane potential that usefluorescence resonance energy transfer” Chem Biol 4(4): 269-77) incombination with instrumentation for measuring fluorescence changes suchas the Voltage/Ion Probe Reader (VIPR) (See, Gonzalez, J. E., K. Oades,et al. (1999) “Cell-based assays and instrumentation for screeningion-channel targets” Drug Discov Today 4(9): 431-439).

These voltage sensitive assays are based on the change in fluorescenceresonant energy transfer (FRET) between the membrane-soluble,voltage-sensitive dye, DiSBAC₂(3), and a fluorescent phospholipid,CC2-DMPE, which is attached to the outer leaflet of the plasma membraneand acts as a FRET donor. Changes in membrane potential (V_(m)) causethe negatively charged DiSBAC₂(3) to redistribute across the plasmamembrane and the amount of energy transfer from CC2-DMPE changesaccordingly. The changes in fluorescence emission were monitored usingVIPR™ II, which is an integrated liquid handler and fluorescent detectordesigned to conduct cell-based screens in 96- or 384-well microtiterplates.

Identification of Correction Compounds

To identify small molecules that correct the trafficking defectassociated with ΔF508-CFTR; a single-addition HTS assay format wasdeveloped. The cells were incubated in serum-free medium for 16 hrs at37° C. in the presence or absence (negative control) of test compound.As a positive control, cells plated in 384-well plates were incubatedfor 16 hrs at 27° C. to “temperature-correct” ΔF508-CFTR. The cells weresubsequently rinsed 3× with Krebs Ringers solution and loaded with thevoltage-sensitive dyes. To activate ΔF508-CFTR, 10 μM forskolin and theCFTR potentiator, genistein (20 μM), were added along with Cl⁻-freemedium to each well. The addition of Cl⁻-free medium promoted C⁻ effluxin response to ΔF508-CFTR activation and the resulting membranedepolarization was optically monitored using the FRET-basedvoltage-sensor dyes.

Identification of Potentiator Compounds

To identify potentiators of ΔF508-CFTR, a double-addition HTS assayformat was developed. During the first addition, a Cl⁻-free medium withor without test compound was added to each well. After 22 sec, a secondaddition of Cl⁻-free medium containing 2-10 μM forskolin was added toactivate ΔF508-CFTR. The extracellular Cl⁻ concentration following bothadditions was 28 mM, which promoted Cl⁻ efflux in response to ΔF508-CFTRactivation and the resulting membrane depolarization was opticallymonitored using the FRET-based voltage-sensor dyes.

Solutions

Bath Solution #1: (in mM) NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10,pH 7.4 with NaOH. Chloride-free bath solution: Chloride salts in BathSolution #1 are substituted with gluconate salts.

CC2-DMPE: Prepared as a 10 mM stock solution in DMSO and stored at −20°C. DiSBAC₂(3): Prepared as a 10 mM stock in DMSO and stored at −20° C.

Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used foroptical measurements of membrane potential. The cells are maintained at37° C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For all opticalassays, the cells were seeded at 30,000/well in 384-well matrigel-coatedplates and cultured for 2 hrs at 37° C. before culturing at 27° C. for24 hrs. for the potentiator assay. For the correction assays, the cellsare cultured at 27° C. or 37° C. with and without compounds for 16-24hours B) Electrophysiological Assays for assaying ΔF508-CFTR modulationproperties of compounds

1. Using Chamber Assay

Using chamber experiments were performed on polarized epithelial cellsexpressing ΔF508-CFTR to further characterize the ΔF508-CFTR modulatorsidentified in the optical assays. FRTΔF508-CFTR epithelial cells grownon Costar Snapwell cell culture inserts were mounted in an Using chamber(Physiologic Instruments, Inc., San Diego, Calif.), and the monolayerswere continuously short-circuited using a Voltage-clamp System(Department of Bioengineering, University of Iowa, IA, and, PhysiologicInstruments, Inc., San Diego, Calif.). Transepithelial resistance wasmeasured by applying a 2-mV pulse. Under these conditions, the FRTepithelia demonstrated resistances of 4 KΩ/cm² or more. The solutionswere maintained at 27° C. and bubbled with air. The electrode offsetpotential and fluid resistance were corrected using a cell-free insert.Under these conditions, the current reflects the flow of Cl⁻ throughΔF508-CFTR expressed in the apical membrane. The Isc was digitallyacquired using an MP100A-CE interface and AcqKnowledge software (v3.2.6;BIOPAC Systems, Santa Barbara, Calif.).

Identification of Correction Compounds

Typical protocol utilized a basolateral to apical membrane Cl⁻concentration gradient. To set up this gradient, normal ringer was usedon the basolateral membrane, whereas apical NaCl was replaced byequimolar sodium gluconate (titrated to pH 7.4 with NaOH) to give alarge Cl⁻ concentration gradient across the epithelium. All experimentswere performed with intact monolayers. To fully activate ΔF508-CFTR,forskolin (10 μM) and the PDE inhibitor, IBMX (100 μM), were appliedfollowed by the addition of the CFTR potentiator, genistein (50 μM).

As observed in other cell types, incubation at low temperatures of FRTcells stably expressing ΔF508-CFTR increases the functional density ofCFTR in the plasma membrane. To determine the activity of correctioncompounds, the cells were incubated with 10 μM of the test compound for24 hours at 37° C. and were subsequently washed 3× prior to recording.The cAMP- and genistein-mediated I_(SC) in compound-treated cells wasnormalized to the 27° C. and 37° C. controls and expressed as percentageactivity. Preincubation of the cells with the correction compoundsignificantly increased the cAMP- and genistein-mediated I_(SC) comparedto the 37° C. controls.

Identification of Potentiator Compounds

Typical protocol utilized a basolateral to apical membrane Cl⁻concentration gradient. To set up this gradient, normal ringers was usedon the basolateral membrane and was permeabilized with nystatin (360μg/ml), whereas apical NaCl was replaced by equimolar sodium gluconate(titrated to pH 7.4 with NaOH) to give a large Cl⁻ concentrationgradient across the epithelium. All experiments were performed 30 minafter nystatin permeabilization. Forskolin (10 μM) and all testcompounds were added to both sides of the cell culture inserts. Theefficacy of the putative ΔF508-CFTR potentiators was compared to that ofthe known potentiator, genistein.

Solutions

Basolateral NaCl (135), CaCl₂ (1.2), MgCl₂ (1.2), K₂HPO₄ (2.4), solutionKHPO₄ (0.6), N-2-hydroxyethylpiperazine-N′-2- (in mM): ethanesulfonicacid (HEPES) (10), and dextrose (10). The solution was titrated to pH7.4 with NaOH. Apical solution Same as basolateral solution with NaClreplaced with Na (in mM): Gluconate (135).

Cell Culture

Fisher rat epithelial (FRT) cells expressing ΔF508-CFTR(FRT^(ΔF508-CFTR)) were used for Using chamber experiments for theputative ΔF508-CFTR modulators identified from our optical assays. Thecells were cultured on Costar Snapwell cell culture inserts and culturedfor five days at 37° C. and 5% CO₂ in Coon's modified Ham's F-12 mediumsupplemented with 5% fetal calf serum, 100 U/ml penicillin, and 100μg/ml streptomycin. Prior to use for characterizing the potentiatoractivity of compounds, the cells were incubated at 27° C. for 16-48 hrsto correct for the ΔF508-CFTR. To determine the activity of correctionscompounds, the cells were incubated at 27° C. or 37° C. with and withoutthe compounds for 24 hours.

2. Whole-Cell Recordings

The macroscopic ΔF508-CFTR current (I_(ΔF50)) in temperature- and testcompound-corrected NIH3T3 cells stably expressing ΔF508-CFTR weremonitored using the perforated-patch, whole-cell recording. Briefly,voltage-clamp recordings of IΔF508 were performed at room temperatureusing an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.,Foster City, Calif.). All recordings were acquired at a samplingfrequency of 10 kHz and low-pass filtered at 1 kHz. Pipettes had aresistance of 5-6 MΩ when filled with the intracellular solution. Underthese recording conditions, the calculated reversal potential for Cl⁻(E_(C1)) at room temperature was −28 mV. All recordings had a sealresistance >20 GΩ and a series resistance <15 MΩ. Pulse generation, dataacquisition, and analysis were performed using a PC equipped with aDigidata 1320 A/D interface in conjunction with Clampex 8 (AxonInstruments Inc.). The bath contained <250 μl of saline and wascontinuously perifused at a rate of 2 ml/min using a gravity-drivenperfusion system.

Identification of Correction Compounds

To determine the activity of correction compounds for increasing thedensity of functional ΔF508-CFTR in the plasma membrane, we used theabove-described perforated-patch-recording techniques to measure thecurrent density following 24-hr treatment with the correction compounds.To fully activate ΔF508-CFTR, 10 μM forskolin and 20 μM genistein wereadded to the cells. Under our recording conditions, the current densityfollowing 24-hr incubation at 27° C. was higher than that observedfollowing 24-hr incubation at 37° C. These results are consistent withthe known effects of low-temperature incubation on the density ofΔF508-CFTR in the plasma membrane. To determine the effects ofcorrection compounds on CFTR current density, the cells were incubatedwith 10 μM of the test compound for 24 hours at 37° C. and the currentdensity was compared to the 27° C. and 37° C. controls (% activity).Prior to recording, the cells were washed 3× with extracellularrecording medium to remove any remaining test compound. Preincubationwith 10 μM of correction compounds significantly increased the cAMP- andgenistein-dependent current compared to the 37° C. controls.

Identification of Potentiator Compounds

The ability of ΔF508-CFTR potentiators to increase the macroscopicΔF508-CFTRCl⁻ current (I_(ΔF508)) in NIH3T3 cells stably expressingΔF508-CFTR was also investigated using perforated-patch-recordingtechniques. The potentiators identified from the optical assays evoked adose-dependent increase in I_(ΔF508) with similar potency and efficacyobserved in the optical assays. In all cells examined, the reversalpotential before and during potentiator application was around −30 mV,which is the calculated E_(C1) (−28 mV).

Solutions

Intracellular Cs-aspartate (90), CsCl (50), MgCl₂ (1), HEPES (10), andsolution 240 μg/ml amphotericin-B (pH adjusted to 7.35 with (in mM):CsOH). Extracellular N-methyl-D-glucamine (NMDG)-Cl (150), MgCl₂ (2),solution CaCl₂ (2), HEPES (10) (pH adjusted to 7.35 with HCl). (in mM):

Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forwhole-cell recordings. The cells are maintained at 37° C. in 5% CO₂ and90% humidity in Dulbecco's modified Eagle's medium supplemented with 2mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME, 1× pen/strep, and 25mM HEPES in 175 cm² culture flasks. For whole-cell recordings,2,500-5,000 cells were seeded on poly-L-lysine-coated glass coverslipsand cultured for 24-48 hrs at 27° C. before use to test the activity ofpotentiators; and incubated with or without the correction compound at37° C. for measuring the activity of correctors.

3. Single-Channel Recordings

The single-channel activities of temperature-corrected ΔF508-CFTR stablyexpressed in NIH3T3 cells and activities of potentiator compounds wereobserved using excised inside-out membrane patch. Briefly, voltage-clamprecordings of single-channel activity were performed at room temperaturewith an Axopatch 200B patch-clamp amplifier (Axon Instruments Inc.). Allrecordings were acquired at a sampling frequency of 10 kHz and low-passfiltered at 400 Hz. Patch pipettes were fabricated from Corning KovarSealing #7052 glass (World Precision Instruments, Inc., Sarasota, Fla.)and had a resistance of 5-8 MΩ when filled with the extracellularsolution. The ΔF508-CFTR was activated after excision, by adding 1 mMMg-ATP, and 75 nM of the cAMP-dependent protein kinase, catalyticsubunit (PKA; Promega Corp. Madison, Wis.). After channel activitystabilized, the patch was perifused using a gravity-drivenmicroperfusion system. The inflow was placed adjacent to the patch,resulting in complete solution exchange within 1-2 sec. To maintainΔF508-CFTR activity during the rapid perifusion, the nonspecificphosphatase inhibitor F⁻ (10 mM NaF) was added to the bath solution.Under these recording conditions, channel activity remained constantthroughout the duration of the patch recording (up to 60 min). Currentsproduced by positive charge moving from the intra- to extracellularsolutions (anions moving in the opposite direction) are shown aspositive currents. The pipette potential (V_(p)) was maintained at 80mV.

Channel activity was analyzed from membrane patches containing ≦2 activechannels. The maximum number of simultaneous openings determined thenumber of active channels during the course of an experiment. Todetermine the single-channel current amplitude, the data recorded from120 sec of ΔF508-CFTR activity was filtered “off-line” at 100 Hz andthen used to construct all-point amplitude histograms that were fittedwith multigaussian functions using Bio-Patch Analysis software(Bio-Logic Comp. France). The total microscopic current and openprobability (PO) were determined from 120 sec of channel activity. ThePO was determined using the Bio-Patch software or from the relationshipP_(o)=I/i(N), where I=mean current, i=single-channel current amplitude,and N=number of active channels in patch.

Solutions

Extracellular NMDG (150), aspartic acid (150), CaCl₂ (5), solution (inmM): MgCl₂ (2), and HEPES (10) (pH adjusted to 7.35 with Tris base).Intracellular NMDG-Cl (150), MgCl₂ (2), EGTA (5), TES (10), and solution(in mM): Tris base (14) (pH adjusted to 7.35 with HCl).

Cell Culture

NIH3T3 mouse fibroblasts stably expressing ΔF508-CFTR are used forexcised-membrane patch-clamp recordings. The cells are maintained at 37°C. in 5% CO₂ and 90% humidity in Dulbecco's modified Eagle's mediumsupplemented with 2 mM glutamine, 10% fetal bovine serum, 1×NEAA, β-ME,1× pen/strep, and 25 mM HEPES in 175 cm² culture flasks. For singlechannel recordings, 2,500-5,000 cells were seeded onpoly-L-lysine-coated glass coverslips and cultured for 24-48 hrs at 27°C. before use.

Compounds of the invention are useful as modulators of ATP bindingcassette transporters. Table 3 below illustrates the EC50 and relativeefficacy of certain embodiments in Table 1.

In Table 3 below, the following meanings apply:

EC50: “+++” means <10 uM; “++” means between 10 uM to 25 uM; “+” meansbetween 25 uM to 60 uM.

% Efficacy: “+” means <25%; “++” means between 25% to 100%; “+++” means>100%.

TABLE 3 EC50 % Cmpd # (uM) Activity 1 +++ ++ 2 +++ ++ 3 +++ ++ 4 +++ ++5 ++ ++ 6 +++ +++ 7 + + 8 +++ ++ 9 + + 10 +++ ++ 11 +++ ++ 12 +++ ++ 13+++ ++ 14 +++ ++ 15 ++ ++ 16 +++ ++ 17 +++ ++ 18 +++ ++ 19 ++ + 20 +++++ 21 + + 22 ++ ++ 23 +++ ++ 24 + + 25 ++ ++ 26 +++ ++ 28 ++ ++ 29 ++ ++30 +++ ++ 31 +++ ++ 32 +++ ++ 33 +++ ++ 34 +++ ++ 35 +++ ++ 36 +++ ++ 37+++ ++ 38 +++ ++ 39 ++ ++ 40 + + 41 +++ ++ 42 +++ ++ 43 +++ ++ 44 ++ ++46 ++ ++ 47 +++ ++ 48 +++ ++ 49 +++ ++ 50 +++ ++ 51 +++ ++ 52 +++ ++53 + + 54 + + 55 + + 56 +++ ++ 57 ++ +++ 58 +++ ++ 59 +++ +++ 60 +++ ++61 +++ ++ 62 +++ ++ 63 +++ ++ 64 + + 65 +++ ++ 66 ++ ++ 67 +++ ++ 68 +++++ 69 +++ ++ 70 ++ ++ 71 +++ ++ 72 +++ ++ 73 + + 74 + + 75 + + 76 +++ ++77 +++ ++ 78 + + 79 +++ ++ 80 +++ ++ 81 + + 82 +++ ++ 83 +++ ++ 84 + +85 +++ ++ 86 ++ ++ 87 +++ ++ 88 +++ ++ 89 + + 90 +++ ++ 91 +++ ++ 92 +++++ 93 +++ ++ 94 +++ ++ 95 ++ ++ 96 +++ ++ 97 +++ ++ 98 +++ ++ 99 +++ ++100 + + 101 +++ ++ 102 ++ ++ 103 +++ +++ 104 +++ ++ 105 ++ ++ 106 + +107 ++ ++ 108 +++ ++ 109 ++ ++ 110 + + 111 +++ ++ 112 +++ ++ 113 +++ ++114 +++ ++ 115 +++ ++ 116 +++ ++ 117 +++ ++ 118 +++ ++ 119 +++ ++ 120 ++++ 122 + + 123 +++ ++ 124 +++ +++ 125 ++ ++ 126 +++ ++ 127 +++ ++128 + + 129 ++ ++ 130 +++ ++ 131 +++ ++ 132 + + 133 ++ ++ 134 +++ ++ 135+++ +++ 136 +++ ++ 137 +++ ++ 138 +++ ++ 139 +++ ++ 140 +++ ++ 141 ++ ++142 +++ ++ 143 +++ ++ 144 +++ ++ 145 +++ ++ 146 + + 147 +++ ++ 148 +++++ 149 ++ ++ 150 +++ ++ 151 +++ ++ 152 + + 153 +++ ++ 154 + + 155 + +156 +++ ++ 157 +++ ++ 158 +++ ++ 159 ++ ++ 160 +++ ++ 161 +++ ++ 162 + +163 ++ ++ 164 +++ ++ 165 + + 166 +++ ++ 167 ++ ++ 168 + + 169 ++ ++170 + + 171 +++ ++ 172 +++ ++ 173 + + 174 +++ ++ 175 ++ ++ 176 +++ ++177 +++ +++ 178 +++ ++ 179 + + 180 +++ ++ 181 +++ ++ 182 +++ ++ 183 +++++ 184 + + 185 + + 186 +++ ++ 187 +++ ++ 188 +++ ++ 189 +++ ++ 190 +++++ 191 + + 192 + + 193 ++ ++ 194 + + 195 + + 196 +++ ++ 197 + + 198 +++++ 199 +++ ++ 200 ++ ++ 201 ++ + 202 +++ ++ 203 +++ ++ 204 +++ ++ 205+++ ++ 206 +++ ++ 207 +++ ++ 208 +++ ++ 209 ++ ++ 210 ++ ++ 211 +++ ++212 + + 213 +++ ++ 214 ++ ++ 215 +++ ++ 216 + + 217 ++ ++ 218 +++ ++219 + + 220 +++ ++ 221 +++ ++ 222 ++ ++ 223 +++ ++ 224 +++ ++ 225 +++ ++226 +++ ++ 227 + + 228 +++ ++ 229 +++ ++ 230 ++ ++ 231 +++ ++ 232 ++ ++233 ++ + 234 +++ ++ 235 +++ ++ 236 +++ ++ 237 +++ ++ 238 +++ ++ 239 +++++ 240 +++ ++ 241 ++ ++ 242 +++ ++ 243 ++ ++ 244 +++ ++ 245 +++ ++ 246+++ ++ 247 +++ ++ 248 ++ ++ 249 ++ ++ 250 + + 251 +++ ++ 252 ++ ++ 253+++ ++ 254 +++ ++ 255 +++ ++ 256 + + 257 +++ ++ 258 +++ ++ 259 +++ ++260 +++ ++ 261 +++ ++ 262 +++ ++ 263 +++ ++ 264 ++ ++ 265 +++ ++ 266 +++++ 267 +++ ++ 268 ++ ++ 269 +++ ++ 270 +++ ++ 271 +++ ++ 272 ++ ++ 273+++ +++ 274 +++ ++ 275 ++ ++ 276 ++ ++ 277 +++ +++ 278 +++ ++ 279 +++ ++280 + + 281 +++ ++ 282 +++ ++ 283 +++ +++ 284 ++ ++ 285 +++ ++ 286 ++++++ 287 +++ ++ 288 +++ ++ 289 +++ ++ 290 +++ ++ 291 +++ ++ 292 +++ ++293 ++ +++ 294 ++ ++ 295 +++ ++ 296 ++ ++ 297 +++ ++ 298 +++ ++ 299 +++++ 300 +++ ++ 301 + + 302 ++ ++ 303 ++ ++ 304 +++ ++ 305 +++ +++ 306 ++++++ 307 +++ ++ 308 ++ ++ 309 + + 310 +++ ++ 311 +++ ++ 312 +++ ++ 313+++ ++ 314 +++ ++ 315 +++ ++ 316 ++ ++ 317 +++ ++ 318 ++ ++ 319 +++ ++320 +++ ++ 321 +++ ++ 322 +++ ++ 323 +++ ++ 324 +++ ++ 325 +++ ++ 326 ++++ 327 +++ ++ 328 + + 329 ++ ++ 330 +++ ++ 331 + + 332 +++ ++ 333 +++ ++334 ++ ++ 335 + + 336 +++ ++ 337 +++ ++ 338 ++ ++ 339 +++ ++ 340 +++ ++341 +++ ++ 342 +++ ++ 343 ++ ++ 344 +++ ++ 345 +++ ++ 346 +++ ++ 347 ++++ 348 +++ ++ 350 +++ ++ 351 +++ ++ 352 +++ ++ 353 +++ ++ 354 +++ ++ 355+++ ++ 356 +++ ++ 357 +++ ++ 358 +++ ++ 359 ++ ++ 360 +++ ++ 361 +++ +++362 +++ ++ 363 +++ +++ 364 +++ ++ 365 ++ ++ 366 +++ ++ 367 +++ ++ 368+++ ++ 369 ++ + 370 +++ ++ 371 +++ ++ 372 +++ ++ 373 +++ ++ 374 + + 375+++ ++ 376 + + 377 ++ ++ 378 ++ ++ 379 ++ ++ 380 +++ ++ 381 +++ ++ 382+++ ++ 383 +++ ++ 384 +++ ++ 385 +++ ++ 386 +++ ++ 387 +++ ++ 388 +++ ++389 +++ ++ 390 + + 391 +++ ++ 392 + + 393 +++ ++ 394 + + 395 +++ ++ 396++ ++ 397 +++ ++ 398 ++ ++ 399 +++ ++ 400 + + 401 +++ ++ 402 +++ + 403+++ ++ 404 +++ ++ 405 +++ ++ 406 +++ ++ 407 +++ ++ 408 +++ ++ 409 +++ ++410 +++ +++ 411 +++ ++ 412 +++ ++ 413 +++ ++ 414 + + 415 +++ ++ 416 +++++ 417 +++ ++ 418 ++ ++ 419 + + 420 +++ ++ 421 +++ ++ 423 +++ ++ 424 +++++ 425 +++ ++ 426 +++ ++ 427 +++ ++ 428 +++ ++ 429 +++ ++ 430 +++ ++ 431++ ++ 432 +++ ++ 433 +++ ++ 434 +++ ++ 435 +++ ++ 436 +++ ++ 437 + + 438+++ ++ 439 +++ ++ 440 +++ ++ 441 +++ ++ 442 + + 443 + + 444 +++ ++ 445+++ +++ 446 + + 447 ++ ++ 448 +++ ++ 449 +++ ++ 450 ++ ++ 451 +++ ++ 452+++ ++ 453 +++ ++ 454 + + 455 +++ ++ 456 +++ ++ 457 + + 458 +++ ++ 459+++ ++ 460 +++ ++ 461 +++ ++ 462 +++ ++ 463 +++ ++ 464 +++ ++ 465 +++ ++466 +++ ++ 467 + + 468 + + 469 +++ ++ 470 +++ ++ 471 +++ ++ 472 +++ ++473 ++ ++ 474 + + 476 +++ ++ 477 + + 478 +++ ++ 479 +++ ++ 480 + + 481+++ ++ 482 ++ ++ 483 +++ ++ 484 +++ ++ 485 +++ ++

What is claimed is:
 1. A compound which is B-24


2. A process for the preparation of Compound B-24

comprising contacting 4-tert-butylaniline with N-bromosuccinimide toproduce 2-bromo-4-tert-butylaniline

further contacting 2-bromo-4-tert-butylaniline with a mixture of KNO₃and sulfuric acid to produce 2-bromo-4-tert-butyl-5-nitroaniline

contacting 2-bromo-4-tert-butyl-5-nitroaniline withtrimethylsilylacetylene, Pd(PPh₃)Cl₂, CuI and triethylamine to produce4-tert-butyl-5-nitro-2-((trimethylsilyl)ethynyl)aniline

contacting 4-tert-butyl-5-nitro-2-((trimethylsilyl)ethynyl)aniline withCuI to produce 5-tert-butyl-6-nitro-1H-indole

contacting 5-tert-butyl-6-nitro-1H-indole with Raney Ni in the presenceof hydrogen gas to produce 6-amino-5-tert-butyl-1H-indole (B-24)


3. The process according to claim 2, wherein the N-bromosuccinimide stepfurther comprises a solvent.
 4. The process according to claim 3,wherein the solvent is DMF.
 5. The process according to claim 2, whereinthe trimethylsilylacetylene step further comprises a solvent.
 6. Theprocess according to claim 5, wherein the solvent is a mixture oftoluene and water.
 7. The process according to claim 6, wherein theratio of toluene to water in the mixture is about 2:1.
 8. The processaccording to claim 2, wherein the step to produce5-tert-butyl-6-nitro-1H-indole further comprises a solvent.
 9. Theprocess according to claim 8, wherein the solvent is DMF.
 10. Theprocess according to claim 9, wherein the chemical reaction is performedat a temperature from about 120° C. to about 153° C.